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In four studies funded by the NIH and conducted at Columbia
University in New York City during the early 1990s, 68 healthy children and 66
children diagnosed with attention-defi cit/hyperactivity disorder (ADHD) were
enrolled in a nontherapeutic experiment (with no potential direct medical
benefi t). The purpose of the study was to investigate possible correlations
between serotonergic activity and aggression. There are some data to indicate
that an increased secretion of serotonin may be associated with aggression.
Some of these children were identifi ed as having aggressive behavior. The rest
of the children were identifi ed as having potential aggressive behavior
because they had siblings who were incarcerated or had family, social, genetic,
or environmental factors associated with aggressive behavior. The rationale for
this experiment is that administering a dose of fenfl uramine could greatly
increase the rate of secretion of serotonin in the experimental group compared
with the control group, which could reveal an association between serotonergic
activity and aggressive behavior. Fenfl uramine is one of the active components
of the “Fen-Phen” antiobesity drug combination, which has signifi cant known
risks, such as cardiac damage. ADHD itself is recognized as a risk factor for
aggression. All children were African Americans or Latinos from very poor
environments, and all were receiving drug treatment. The children were given a
gift certifi cate of $25, and the parents were given $100 to $150 each. Incarcerated
siblings were identifi ed from sealed court records without permission from the
courts or the city administration. Afterward, the researchers contacted the
subjects and their siblings at their homes and identifi ed themselves as
persons conducting research funded by the federal government. The study was
approved by several IRBs. NIH study sections also approved the original
research proposal. The procedure required subjects to undergo a battery of
tests, including genetic tests. The subjects then underwent an overnight fast
and were administered a challenge dose of fenfl uramine, with blood samples
collected for several hours. Samples of spinal fl uid (by spinal taps) were
collected every 3 hours for 12 hours. Blood levels of serotonin were monitored continuously
through a vein catheter. Because the study offered no potential direct medical
benefi ts, it could not be approved under the federal designation 45 CFR 46.404
or 46.405 (category I or II). It could only be approved under designations
46.406 or 46.407 (category III or IV; see defi nitions above). In the fall of
1997, the human rights organization, Citizens for Responsible Care and Research
(CIRCARE), cofounded by one of the authors (Shamoo), called for an
investigation by the federal oversight agency, the Offi ce of Protection from
Research Risks (OPRR), the predecessor of the Offi ce for Human Research
Protections. CIRCARE also alerted the media and other advocacy groups. The
determination letter from OPRR claimed that using healthy subjects was
appropriate, whereas using ADHD subjects was not appropriate. Also, OPRR said
that the informed consent document did not adequately inform the parents.
Unfortunately, the OPRR determination was based on technical matters such as
whether there was a properly convened meeting of the IRB, not on substantive
matters concerning the ethics of the study (Shamoo and Tauer 2002, Koocher
2005).
• Were the risks to subjects minimized?
• Were the benefi ts suffi cient to justify the study?
• What kind of informed consent process could be adequate?
• Was the selection of subjects equitable?
• Was confi dentiality of subjects, family, or their
siblings protected?
• What can we learn from this episode?

Lead poison is a serious problem in houses built prior to 1980.
There are data to indicate that lead poisoning in children causes serious defi
cits in the neurodevelopment. Between 1995 and 1998, investigators from the
Kennedy Krieger Institute (KKI) at Johns Hopkins University enrolled 50 poor
families with very young children living in Baltimore for a lead abatement
experiment. The families were randomly assigned to receive one of three
different abatement programs to reduce lead, or to be in one of two control
groups. The three different abatement programs, which were less expensive than
complete lead abatement, ranged in cost from $1,650 to $7,000. The two control
groups included one group of families with full lead abatement and one living
in housing without lead paint. The recruited families had children ranging in
age from 6 months to 7 years. The investigators collaborated with the landlords
on this experiment. Landlords were encouraged to recruit families with young
children and in some cases were told that they must have young children. The
investigators helped the landlords apply for grants for ead abatement. The lead
level in each house was measured by wipe tests and air samples. Each house was
tested before and after abatement and while the families were living in these
houses. The blood level of lead in each child was also measured at different
time periods. The informed consent document stated that once the investigators
know the child’s blood lead level, “we would contact you to discuss a summary
of house test results and steps that you could take to reduce any risks of
exposure.” The study was sponsored by the EPA and the Maryland Department of
Housing and Community Development. Families of two children sued the KKI for
negligence. The suit alleged that the investigators failed to inform the
parents in a timely fashion about dangerous lead levels and failed to provide
adequate informed consent (Grimes v. Kennedy Krieger Institute, Inc. 2001). One
of the children, Erika Grimes, was ten months old when she fi rst lived in the
house, and the other child, Myron Higgins, was three and a half years old. The
acceptable lead level for a child is 10 µg/dl. KKI found that Erika Grimes’s
blood level was higher than normal. The allegations are that KKI waited nine
months to inform the Grimes family. Her original blood level was 9 µg/dl and
subsequently her blood level was 32 µg/dl and 22 µg/dl. Medical treatment or
intervention is indicated at 25 µg/dl. Erika then was moved out of the house.
The defendants moved to dismiss the case, on the grounds that the researchers
had no legal duties to the subjects that could justify a negligence claim. The
circuit court agreed. The plaintiffs appealed the case to the Maryland Court of
Special Appeals. The appellate court overruled the lower court’s decision on
the grounds that the investigators had legal duties to the research subjects
because they have a “special relationship” with the subjects. The appellate
court remanded the case to the circuit court for fi nding consistent with its
opinion, and opined that children can only participate in research that poses
no risk or research in which they are expected to receive a direct medical
benefi t. This opinion sent shock waves through the research community, as it
would invalidate (in the State of Maryland) research conducted in accordance
with 45 CFR 46.405–407. In response to a swell of protest from research
institutions, the appellate court issued a clarifi cation that their order does
not bar children’s participation in nontherapeutic research with minimal risk.
In discussing the case, the appellate court also stated: “There was no complete
and clear explanation in the consent agreements signed by the parents of the
children that the research to be conducted was designed, at least in signifi
cant part, to measure the success of the abatement procedure.” The court went
further and showed its dismay at the design of the study and stated that
“researchers intended that the children be the canaries in the mines, but never
clearly told the parents” (Shamoo 2002; see also Kopelman 2002).
• What regulatory rule would govern this study, and which
section?
• Were the risks minimized?
• Were the risks justifi ed in relation to benefi ts?
• Was the selection of subjects equitable?
• Was informed consent adequate?

The aim of a study is to better understand condom use among
adolescents and the psychosocial factors that increase or decrease condom use.
The study is a survey of adolescent attitudes and beliefs about sexuality. It
will include many different questions about sexuality as well as questions
about alcohol and drug use, violence, musical tastes, and religion. The
subjects will not be told the exact purpose of the study when they take the
survey, but they will be told the results of the study. Subjects will be
recruited from three local high schools. Personal identifi ers will be removed
for data analysis and publication. High school health education teachers will
help administer the survey. Taking the survey will suffi ce as proof of
consent. Subjects may refuse to take the survey without penalty. Parents will
be notifi ed about the study and may refuse to allow their children to
participate.
• In what specifi c category of risk (discussed above) would
you place this protocol? Why?
• How would you protect the privacy of subjects?
• Why should the parents be involved?
• Should the community be concerned?