May 15, 2003
Bernard Schwetz, D.V.M., Ph.D.
Acting Director,
Office for Human Research Protections
The Tower Building
1101 Wooten Parkway, Suite 200
Rockville, MD 20852
Doctor Schwetz:
I appreciate the opportunity to review the protocol for
the study of “Sleep Mechanisms in Children: Role of the Metabolism.”
In addition to attending the panel review of 6 May,
2003, I have reviewed RFA HL-01-006, the protocol, informed consent documents
and considered the scientific discussion. I conclude that the research
described therein is not approvable under 45 CFR 46.404, 46.405, or 46.406.
My comments address why I perceive this protocol
generates more than minimal risk to the participant without adequate corresponding
prospect of benefit which excludes the protocol from approval under 46.404,
46.405 and 46.406.
I do not believe the research is approvable under 45
CFR 46.407 with modification of the both the protocol and informed consent.
I. Research
not approvable under 45 CFR 46.404, 46.405, or 46.406:
A. More than minimal risk:
Because this protocol
involves more than minimal risk with no direct benefit to healthy volunteer
children, I do not find that it meets any of these provisions for approval
under the federal rules. This protocol clearly and realistically involves the prospect
of complications more serious “than those ordinarily encountered [by children]
in daily life.” 46.102(i).
B.
Risks and inconveniences not addressed:
I do not believe that the
risks associated with participation in this trial are life threatening but I
feel they are certainly greater than those encountered in a child’s daily life.
I am particularly concerned about the behavior and risks this age group (13-17
yrs) might encounter after release from the clinical environment while still in
a significant sleep-deprived state. The obligation to extend supervision or
guarantee physical protection—at least until the child returns to their home--seems
a reasonable one, for example. Attaining both the guardian and participant’s agreement
that they will not drive or operate machinery for a period of time could
minimize this risk. Provision for the journey home (taxi voucher, etc.), would
be a welcome addition to the protocol, especially since financial compensation
will not take place until the conclusion of the child’s role.
C.
Symptoms of sleep deprivation not clearly described:
It is to be expected that
trial participants will temporarily suffer the typical symptoms of sleep
deprivation such as irritability, edginess, inability to tolerate stress,
problems with concentration and memory, behavioral or social problems, blurred
vision, alterations in appetite and activity intolerance. The risk associated
with the sleep deprivation state is greater than a child of this age group would
normally encounter. The symptoms are likely to cause both physical and
emotional discomfort and frustration which qualifies this protocol as one which
would cause more than minimal risk. I do not find the study accurately
describes the symptoms in the risks section of the consent.
D.
Timeline not clearly described in the consent:
The wording of the
“procedures” section of the consent is vague and does not clearly indicate the
length of time the child will need to be at the institution or the wakeful
hours in total.
E.
Risk to Others:
The protocol should also be
seen as posing more than minimal risk because individuals other than the trial
participants may suffer harm due to the behavior and decisions made by the
adolescent after they depart the clinical setting. There is no guarantee that
the minors involved in the study will be under the direct supervision of a
responsible adult until they have totally recuperated from their sleep-deprived
state. Therefore, it would be prudent to realize the subjects could cause harm
to another person, perhaps unwittingly, such as in driving an automobile or
using machinery in an impaired state. Merely identifying sleep deprivation as a
risk falls short.
F.
Adult vs. Child study:
It is acknowledged that
there is a paucity of information known about the role of metabolism in
children during sleep. A great deal could certainly be learned from the data
this study would potentially generate. The fact, however, that this methodology
has not been tested in the adult population yet, is a cause for concern. It
seems reasonable that the safety of the techniques proposed in the study should
be evaluated in the adult population prior to proceeding with study of the
juvenile population. (One questions the extent of the adolescent’s ability to
understand what the effects of 52+ hours of sleep deprivation will feel like, and
if they can indeed make an informed consent decision.)
G.
Financial Incentive:
The pressure of economic
incentive to metropolitan children could be great enough to cause the candidate
or their guardians to accept participation notwithstanding the risks. Additionally,
the family’s financial gain seems inordinately large in comparison to the
participant’s. Ascent of the minor should be taken privately and after showing
the child the magnet, giving them the opportunity to decline for any reason citing
anxiety associated with the device to protect their confidentiality, if
necessary.
H. Adverse Academic Situation:
Although this study is
focused on children in an age group that ordinarily attends school, the study
did not address school or plans for the student to maintain their academic
progress. The risk statement, “You also should not be tested the night before
school,” implies the adolescent might plan attend school following sleep
deprivation, which is not likely. Unless the study is accomplished during a
long break from school, such as summer, it is reasonable to expect the study’s
two 52+ hour visits will interfere with the student’s academic pursuits, unless
they are home instructed and adjust their schedule appropriately.
I. Recruitment Method and
Mechanism:
The recruitment
documentation was not available to review. In an effort to reach all strata of
socioeconomic population, I recommended that internet recruitment be included
and home instructed students be made aware of the opportunity to participate.
If there is any indirect benefit to be derived from a child’s participation in
this study, it could be argued that a home instructed student with an interest
in science might be the best candidate for several reasons implied above.
II. Research
approvable under 45 CFR 46.407, with protocol/informed consent modifications:
The research presents a
reasonable opportunity to further understanding, prevention, or alleviation of
a serious problem affecting the health or welfare of children.
To my lay understanding,
the research presents an opportunity
to further understanding, prevention, or alleviation of a serious problem
affecting the health or welfare of children; however I do not believe it is a reasonable one. The concepts are
scientifically valid, but the timeliness of the test durations and the
feasibility of maintaining a child in a sleep deprived state for 52+ hours are
questionable. The protocol information
states, “None of the studies proposed have been done in adults or children.” This fact causes concern about the
feasibility of analyzing the data and ethics of beginning with children rather
than consenting adults. The approach of the protocol which aims to, “…study
children of various ages, from the very young infant to the adult,” calls into
question the ethical approach of starting with the 13-17 year old group for,
“simplicity and for practical and safety reasons.” It is unlikely that there
would be logical support for conducting this study on a healthy infant;
therefore I also question the argument for selecting the 13-17 year old group.
III. Other
Comments:
1. Possibly reconsider the monetary compensation amounts and/or
division of funds between child and guardian. The guardian’s portion may be
coercive to individuals, especially those from less advantaged income groups.
2. It seems inappropriate
to place the “Payment for Joining the Study,” section in the informed consent
before the risks and benefits section. I recommend it be moved to the “Costs to
You” section near the end of the consent.
3. The statement, “There are
no costs to you,” should be removed from the “Costs to You” section because the family may incur unforeseen
costs such as tutoring or loss of the child’s or guardian’s income during
transportation or appointments.
4. If this study goes
forward, recommend internet recruitment be considered. This would be especially
helpful to provide exposure of the study to gifted and talented program
students, home instructed children and students who have attended community
college “medical school” type of summer programs. These children would be less
likely to be academically set back and more prepared to understand the medical
process and derive some indirect benefit from their participation, which is a
goal.
In conclusion, I support the pursuit of research to study
the role of metabolism in sleep of children and adults. However I find the
length sleep deprivation proposed in this study, when considered with the inclusive
clinical hours and transportation to the center to be problematic and
ultimately unacceptable. If research is
to be conducted on children that requires extensive sleep deprivation, (>24
hours), however, it should be limited to the smallest number of subjects
required to obtain sufficient data.
I appreciate the opportunity to comment on this interesting
research protocol and hope that these comments
are helpful. Thank you for the chance to participate
in the public discussion of this study.
Respectfully,
Colleen M. O’Brien