Conflicts of Interest in Biomedical Research Harm Children With and Without Disabilities

Abstract

Children have been exposed to unjustifiable risks that in some cases amount to research abuse. Powerful, financially interconnected stakeholders control all facets of research, including the approval process. Physician investigators, their academic institutions, and institutional review boards (IRBs) all come under the influence of funding sponsors, whose interests conflict with the best interest of children. Children cannot rely on IRBs or on any of the existing research oversight agencies to protect them, for research too often takes inordinate risks in the name of the greater good.

Full text

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Journal of Disability Policy Studies
Vol. 15, No. 1, 50-59 (2004)
Conflicts of Interest in Biomedical Research
Harm Healthy and Disabled Children
Vera Hassner Sharav, M.L.S.
ABSTRACT
Children have been exposed to unjustifiable risks that in some cases amount to “research
abuse.” Powerful, financially interconnected stakeholders control all facets of research, including
the approval process. Physician investigators, their academic institutions, and institutional review
boards (IRBs) all come under the influence of funding sponsors, whose interests conflict with
best interest of children. Children cannot rely on IRBs or any of the existing research oversight
agencies to protect them, for research too often takes inordinate risks in the name of the greater
good.

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Medical research, by its nature involves risks. Infants and children cannot assess those
risks. Neither can they exercise the adult human right to refuse consent to research. They are
thus particularly vulnerable to experiments involving pain, discomfort and risks of medical,
physical and psychological harm. Children are vulnerable to exploitation in “heroic”
experiments, ventures whose risks are not justified by any evidence of foreseeable benefits to the
subjects. (Bailey 1985; Anas 1985; Kushner 1985). History demonstrates that the welfare of
vulnerable persons—such as the mentally retarded or incapacitated, minorities, the economically
disadvantaged, and children from poor families—have been compromised, their rights violated,
even when codified ethical standards for the protection individual rights exist (ACHRE, 1995).
The absence of an effective system of protection for human subjects is a serious defect
in the biomedical research enterprise. Federal oversight agencies—the Office of Human
Research Protections (OHRP), the General Accounting Office (1996, 2001), the Office of the
Inspector General of the Department of Health and Human Services (1998, 2000)— and the
National Bioethics Advisory Committee (2001), and the Institute of Medicine of the National
Academies (IOM) (2002) have all reported systemic weakness and ethical violations in the
conduct of human subjects research. The IOM report concludes:
“. . . the evidence is abundant regarding the significant strains and weaknesses of
the current system, and this committee has reached the conclusion that major
reforms are in order…. the existing regulatory framework . . . cannot adequately
respond to the complex and ever-changing research environment, with
weaknesses related to gaps in authority, structure, and resources." (p. ES-3-4)
Federal regulations restrict the use of children in research of greater than minimal risk .
The regulations define “minimal risk” as risk on a par with activities “ ordinarily encountered in

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daily life or during the performance of routine physical or psychological examinations or tests”
(45 CFR 46.102(i). Institutional review boards IRBs) may approve research involving “greater
than minimal risk” for children only if the research presents the prospect of direct benefit and
evidence of a favorable risk/ benefit ratio. If there is a “minor increase” over minimal risk and no
prospect of direct benefit for child subjects, investigators must provide compelling evidence that
the research “is likely” to provide essential knowledge, which is of “vital importance” for “the
subjects’ disorder or condition.” (45 CFR 46.406)
The regulations, unfortunately, do not define either “risk,” “greater than minimal risk,”
“condition,” or “benefit.” The life-safety of human subjects may be undermined by inconsistent
and widely disparate interpretations of regulations. (Glantz 1998) Powerful institutions whose
interests conflict with those of research subjects control all facets of research, including the
approval process. (Bodenheimer 2000; Angell, 2000; Kassirer, 2001; Rellman and Angell, 2002)
Failure to review research proposals from “the child’s best interest” perspective, failure to
examine alternative treatments to minimize the exposure of children to research risks, failure to
set limits on the level of risk and pain to which a child may legitimately be exposed—all flow
from pervasive conflicts of interest. Absence of accountability, dependable enforcement
mechanisms, and meaningful penalties invite noncompliance with safety requirements.
Those who have argued that clinical trials involving greater than minimal risk for
children are approvable, even without a prospect of direct benefit, claim that failure to test drugs
in children harms other children who are prescribed drugs off-label (AAP 1995 Milne 2001).
Freedman and colleagues (1993) claim that “a prohibition on such research involvement would
be to the long-term detriment of children, just as a prohibition on new experiences is harmful to
children over the long term.” Others disagree, pointing out that those making such claims fail to

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explain why a particular child not participating in nontherapeutic research would be harmed.
(Ross 2003). Further, few who claim that the benefits to be gained for all children outweigh the
risks for the child subjects (“The Need to Test” 2002) are themselves free of conflicts of interest.
The federal government, through its several advisory panels, such as the National Human
Research Protections Advisory Committee (NHRPAC), set about to deconstruct federal
regulatory restrictions that were enacted to protect children from exposure to undue risk of harm.
(Sharav 2003a) For example, the Children’s Workgroup of NHRPAC recommended that the
“minimal risk” category be broadened: “IRBs need not limit the tests or procedures in the
research to those actually used in routine physical or psychological evaluations” (Fleischman
2002, p.2). Instead, the Workgroup of largely academic stakeholders—with the exception of one
dissenting community representative—favored giving IRBs greater latitude to interpret minimal
risk based on their notion of an indeterminate concept, they call, "equivalence of risk."
Another recommendation would waive parental permission by elevating children’s “assent”
to the level of informed consent (NHRPAC 2001). But children who are enrolled in clinical
research are not legally authorized to volunteer for experimental research. [45 CFR 46.116, 408]
Children, by definition, are non-consensual human subjects who require added protections (US
DHHS 1973). Efforts to circumvent parental authority by elevating the validity of children’s
“assent” for research would abrogate the basic legal doctrine of informed consent, which may be
exercised by adults only. Substituting “assent” for parental “permission” would shift to children
the burden of adult responsibility for decisions judged to be in the best interest of the individual
child.
The rationale for exposing children to research risks is based on utilitarian ethics, which
holds that the sacrifices of the few are necessary to promote the greatest good for the greatest

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number. The unanswered question is who has the moral or legal authority to relegate a child to
bear the burden of risks posed by toxic drugs for science or for the benefit of others?
Incentives to Experiment on Children
The Food and Drug Administration Modernization Act (FDAMA) of 1997, extended in
2002 by the Better Pharmaceuticals for Children Act, provides enormous financial incentives to
pharmaceutical companies, who reap a lucrative six-month extension of patent exclusivity if they
test patented drugs in children. For example, a six- month patent extension for the antipsychotic
Zyprexa (sales $3.5 billion) can mean a billion dollars for Eli Lilly. (Eli Lilly 2003) FDAMA has
also stimulated expansion of pediatric drug trials at academic institutions (Steinbrook 2002;
Vitiello, 2001). But Congress failed to balance financial incentives for these stakeholders in the
drug industry with improved safeguards to protect children, who are not autonomous, from the
increased financial pressure to make use of them. Clinical research is a highly profitable venture
as demonstrated by the 600% increase in the number of physicians engaged in clinical drug trials
in 1998 compared to a decade earlier (Morin 2002, p. 78). Physicians who specialize in clinical
trials are handsomely rewarded, earning more than $1 million annually. Some have earned as
much as $10 million dollars (Steklow 1997; Eichenwald 1999; Wilson and Heath 2001).
Contrary to a prohibition in the ethics code of the American Medical Association (1994; 2000),
physicians commonly earn fees of $2,000 to $5,000 per child they refer for clinical trials
(Dembner 2000). Lind (1990) questions whether offering financial incentives of such magnitude
is ethical.
Since passage of FDAMA, the number of child research subjects has grown from about
16,000 in 1997 to about 45,000 in 2001 (Dembner 2001) The FDA acknowledges that before it
adopted the “Pediatric Rule” in 1998, phase 1 trials in children "had been primarily limited to life

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threatening diseases and children who had the disease for which the new drug was being
proposed" (FDA website). After the rule was adopted
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healthy and disabled child subjects have
been increasingly exposed to pain and risk of harm in experiments that may undermine their
welfare. The welfare of children—and adults as well-- is also undermined by the current IRB
system, for it is riddled by conflict of interests (Whitaker 1998; Eichenwald and Kolata 1999;
Kaufman 2000; Heath and Duff, 2002; Lemmens 2003; Sharav 2002, 2003a). A recent survey by
Harvard’s Health Policy Institute concluded, “the fact that almost
half of all faculty IRB
members serve as consultants to industry
raises potential conflicts of interest” (Campbell 2003, p.
836).
Even parents may have interests that conflict with those of their children, so their consent
does not protect children in the way that an adult’s informed consent protects the adult.. The
radiation commission (ACHRE 1995) recognized the potential conflict, as has a U.S. Supreme
Court ruling: “Parents may be free to become martyrs themselves. But it does not follow that
they are free, in identical circumstances, to make martyrs of their children…” (Prince v
Massachusetts1944). Recently, two court decisions followed suit (TD v NYSOMMH 1995;
Grimes v KKI 2001). In the Maryland case, the researchers argued that protective standards
prohibiting the use of children in greater than minimal risk experiments will deprive children of
“an advantage,” and that a prohibition on nontherapeutic experiments will be a “lost opportunity
to cure a disease”(Amici briefs, 2001). The Court rejected their “lost opportunity” argument and
their hypothesized claim of future “benefits” as spurious. Indeed, new drugs are not eliminating
diseases—nor are many of them an improvement over older and cheaper drugs (ABC, 2002;
Burton 2002). Expert critics point out that randomized controlled trials (RCTs) are not designed
to prove a drug’s safety or effectiveness, or to inform clinicians about what is the best treatment

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at what dose. Healy (2002) has shown that RCTs in pediatric trials testing psychotropic drugs,
for example, do not even address scientifically valuable questions. Further, restrictive criteria for
selecting human research subjects (“cherry picking”) invalidate the generalizability of the
findings (Zimmerman 2002). The short duration of most trials and reliance on self-reporting of
adverse effects result in failure to detect uncommon but potentially deadly adverse effects.
Widespread failure to report all findings—including negative findings—renders suspect many
reports of positive results (Klassen 2002; Harris 2003). Drug trials are designed and controlled
by sponsors for the purpose of obtaining FDA approval, which requires merely demonstration of
an effect greater than that of a placebo—which is not necessarily better than an existing
treatment. It can be argued that most clinical trials for which children are currently being
recruited, then randomized to an experimental treatment or placebo, will not improve their
health. Indeed, those who serve as test subjects are at increased risk of harm and discomfort, as
documented in the Boston Globe series reporting how many children suffered and died in
unethical clinical trials (Dembner 2001). Five case examples are presented to illustrate the nature
of the ethical dilemmas that surround biomedical research on children.
Case 1: Assessing lead abatement
In the first case investigators at the Kennedy Krieger Institute (KKI) tested the
effectiveness of varying degrees of lead abatement to reduce the risks of brain damage “for
future generations of children” by exposing 140 infants and children, ranging from 6 months to 4
years of age, to lead dust in partially contaminated houses (EPA 1996). Successful lead
abatement was measured by the extent of lead detected in the blood of children from largely
African American mothers on welfare. The researchers ignored their own findings from a prior
study that showed even “low levels of blood lead in the range seen
in many impoverished inner-

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city children cause structural alterations” in children’s brains. (Wilson 2000, p. 5545). The
investigators, the Johns Hopkins University (JHU) IRB, and state and federal government
agencies justified the risks of lead exposure for these children by invoking a utilitarian rationale,
claiming that sacrifices are necessary for the so-called “greater good.” (Young 2001) That
rationale failed to persuade the judiciary. In August 2001, the Maryland Court of Appeals
(Grimes v KKI 2001) issued a landmark decision that both criticized the experimental design and
rejected current IRB practices geared more toward accommodating the needs of the researchers
than protecting the best interests of the child subjects.
The Court’s decision cited the Nuremberg Code (1947), the Declaration of Helsinki
(1964), and the prevailing “best interest of the child” legal standard. The Court went beyond the
ambiguously defined regulatory standards (45 CFR 46) that IRBs had used to justify the
experiment. Officials of KKI and JHU argued that the focus of the research was to study
buildings, not children; that neither the researchers nor institutions had a duty to warn parents of
the presence of lead dust in the homes; and no duty to warn parents about the danger of increased
lead levels in the children’s blood during the two-year experiment (Roig-Franzia 2001). The
Maryland Court of Appeals summarily rejected all these arguments and sharply rebuked the
researchers, the sponsoring institutions, and the IRBs for their failure to abide by “the best
interest of the child” standard when they exposed little children to the brain-damaging
consequences of increased lead levels in their blood. The Court unambiguously criticized “the
very inappropriateness of the research itself,” a criticism never made by the federal Office of
Human Research Protection (OHRP). The Court reminded researchers, institutions, and IRBs
that they have a “duty of care” for vulnerable human subjects such as children and mentally
incapacitated people, and ruled that “consent of the parents, or any consent surrogates, in our

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view, cannot make the research appropriate or the actions of the researchers and the (IRB)
proper.” (p.7) The Court rejected out-of-hand the often-invoked rationalization that parental
permission absolves researchers and institutions of responsibility for harmful effects suffered by
child subjects, and criticized the practice of giving enticements to parents: “trinkets, food stamps,
money.” The Court set standards for consent and limits on proxy consent, and on parental
authority to consent for research that places children “in potentially hazardous nontherapeutic
research surroundings.” Finally, the Court nullified the absolute authority of researchers “and
their science-based review boards” which, the Court noted, are not “sufficiently objective in the
sense that they are as sufficiently concerned with the ethicality of the experiments they review as
they are with the success of the experiments.” (p. 11)
The hostile reaction of the research community to the decision underscores the extreme
vulnerability of children in the prevailing biomedical research culture (Amici briefs 2001).
Indeed, the Maryland Court compared the deliberate exposure of children to lead dust to sending
“canaries in the mines” to detect the presence of toxic gases. (p. 3) Only one organization, the
Alliance for Human Research Protection, filed an amicus brief in support of the Court of
Appeal’s decision (Amicus brief 2001).
Case 2: “Diabetes prevention” experiments
These trials subject healthy children to invasive, painful glucose tolerance tests before
there is evidence of disease or a proven medical intervention to prevent diabetes. OHRP (2000)
suspended an experiment conducted at the National Institute of Child and Adolescent Human
Development (NICAHD) after determining that there is no justification for exposing healthy
children to such testing. Although all previous prevention experiments failed, they continue to be
conducted. At this stage, diabetes-screening tests involve high risk and no foreseeable benefit. In

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an article entitled Brave New World, Science reports that whereas European scientists are
retreating from diabetes prevention experiments, some American clinicians are forging ahead
with ever more aggressive experimental strategies that expose children to increased risks without
any certainty that these children will even develop diabetes (Couzin 2003). At Columbia
University, children are being exposed experimentally to immunosuppressant therapy (Couzin
2003)—an extremely risky exploratory intervention that can be justified only for those whose
autoimmune system is so over-active as to cause an immune disorder. But the children being
exposed to a radical intervention may as a result suffer the consequences of a compromised
immune system, which would make them vulnerable to acute infection and to debilitating
chronic illness during their entire lives.
These “diabetes prevention” experiments are generating furious debate among
immunologists, endocrinologists, and pediatricians. “How much risk,” they ask, “should we
tolerate in trying to prevent or stall a disease that may not threaten life for many decades?” “How
well must we understand autoimmunity, or a drug’s potential hazards, before treating an 8-year-
old?” (Couzin, 2003, p.1862) Dr. Carla Greenbaum, who directs diabetes clinical research
warns: “We can’t be cowboys on this.” (p. 1862) Proponents of radical interventions in children
seem oblivious to the sobering lessons to be learned from the hormone replacement therapy
debacle (Altman 2003). Who will bear responsibility for the children subjected to radical
experimentation who suffer unintended yet predictable harm as a result of “diabetes prevention”
therapies? The approval of these risky experiments lends support for strict interpretation of
existing Federal regulations to set limits on the level of risk to which children should be exposed.
Additional safeguards are needed to ensure that pediatric research demonstrates with empirical
data a favorable risk / benefit ratio before approval.

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Case 3: Psychostimulant drug trials in preschool children
Dr. Lawrence Diller (2000) described in the Washington Post a case involving a 29-
month toddler, named Simon. “I was flabbergasted when I later learned from his mother that
Simon saw a highly respected child psychiatrist (who prescribed) Lithium, Zoloft, and Risperdal,
three psychiatric drugs at once… I didn't know who felt crazier, Simon or I.” Public concern
about the increasing number of American children being diagnosed with loosely defined
psychiatric “disorders” for which 6 million are prescribed a variety of psychoactive drugs (Safer
1996; Zito 2000; 2002), led to a series of high level conferences in 2000 (Sharav, 2003). At a
workshop convened by the National Institute of Mental Health (NIMH) and the FDA, the
director of Child and Adolescent Treatment and Preventive Interventions Research Branch of
NIMH acknowledged the, “diagnostic uncertainty surrounds most manifestations of
psychopathology in early childhood.” (Vitiello 2001). He also acknowledged that “[t]he impact
of psychotropics on the developing brain is largely unknown, and possible long-term effects of
early exposure to these drugs have not been investigated” (p.983).
Inasmuch as objective diagnostic tools in psychiatry do not exist, experts do not agree
about the criteria for diagnosing children's behavioral disorders. Rating scales and checklists
used do not qualify as scientifically reliable diagnostic tools. Critics—among them, pediatricians,
neurologists, clinical psychologists, and a minority of psychiatrists, suggest that children are
often labeled with a psychiatric “disorder,” such as attention deficit hyperactivity disorder
(ADHD), when their behavior may be within the normal range. Not surprisingly, experts do not
agree about either the diagnostic criteria or the best method for treating children’s behavior
disorders (NIH 1998; Sharav 2003a).

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Psychostimulant drugs that are prescribed for ADHD, such as methylphenidate (Ritalin)
and amphetamine (Adderall, Concerta) carry risks that go well beyond appetite suppression and
sleep disturbance. Stimulants are linked to growth retardation, anxiety and induced psychotic
behavioral episodes in some children (Ravenel 2002). A recent retrospective study found that 6%
of 98 children treated with Ritalin developed psychotic symptoms during treatment (Cherland
1999). These included, paranoia, visual and auditory hallucinations, and bizarre behavior. None
were diagnosed with any other psychiatric disorder before or after treatment with Ritalin, and the
psychotic symptoms resolved following discontinuation of stimulant drugs. Some children
developed obsessive-compulsive disorder (OCD), others had explosive behavioral outbursts
(Kouris 1998). These problematic behaviors were of sufficient severity to discontinue the drug,
whereupon they gradually and completely resolved over two to three months with no recurrence
of OCD behaviors off drugs at one-year follow-up. A case report described a seven-year old boy
who developed both explosive episodes of aggressive and violent behavior, and OCD behavioral
symptoms (Adrian 2001) coincident with treatment with Ritalin. When Ritalin was stopped, both
the explosive and OCD behaviors resolved. Doctors reporting these cases stated that behavioral
problems were induced by Ritalin rather than being a feature of the underlying clinical disorder.
Finally, psychostimulants are controlled Schedule II drugs that carry a serious risk of addiction
(Hyman 1996; Lambert 1998; DEA 2000).
Despite the concerns about known and foreseeable serious risks and the absence of
scientific diagnostic tools, a controversial experiment was launched in 2000 at the 47th annual
meeting of the American Academy of Child and Adolescent Psychiatry at a session entitled,
"New Frontiers in Pediatric Psychopharmacology." The experimental preschool ADHD
treatment study (PATS), a dose tolerance test, is being conducted on children 2 to 5 years old at

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six academic research centers with NIMH funding. Given the risks, one wonders about the
justification that led IRBs at those centers to approve PATS? Did they consider that the
experiment may be used to legitimize 167% increased stimulant drug prescribing for children,
rather than to improve children’s mental health? (Dobbs 2003)
Case 4: Spinal taps for science
This experiment provides a glimpse into the darker side of current psychiatric research
practices involving children who were subjected to pain and risks of spinal taps for
nontherapeutic experimental purposes. In 1996, Dr. Xavier Castellanos (1996) reported the
results of a nine-week, crossover, multiple drug experiment replicating their previous research.
(Castellanos 1994). The 45 boys, aged six to eleven had been diagnosed with ADHD and other
equally controversial behavioral disorders, including "conduct disorder", "oppositional disorder",
and "mild overanxious disorder". The purpose of the experiment was to test the effect of
stimulant drugs (methylphenidate, dextroamphetamine, and placebo) on the cerebrospinal fluid
levels of dopamine, norepinephrine, and serotonin in children. The investigators speculated that
they might find a correlation between dopamine levels and hyperactive behavior. However, they
admitted that there were no criteria for evaluating whether "high” dopamine levels in some
subjects were within the normal range of dopamine levels--thus invalidating possible
conclusions.
Castellanos (1996) reported that originally 54 children had been enrolled in the
experiment, but two who initially agreed, later refused the lumbar puncture. Furthermore, two
children who had previously undergone lumbar puncture "could not be located for reanalysis,"
and four were omitted from the analysis because cerebrospinal fluid (CSF) was "unobtainable"
from them ( p. 126). One wonders how many times the children were subjected to the pain of

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needle jabs in their spine in an effort to obtain spinal fluid, and how the children were prevailed
upon to “assent”? Without explanation the investigators state: “. . .some subjects worsened on
medication compared to placebo” (p. 128). One would want to know how many worsened, in
what way, and whether they recovered. It is unclear why the children were subjected to lumbar
punctures since dopamine is excreted in urine and could have been measured without any pain.
This nontherapeutic experiment and numerous others like it present serious ethical,
methodological and interpretive problems. (Sharav 2003a) Young children are exposed to
considerable pain and unjustifiable risks, to test a speculative hypothesis, not a potential
therapeutic treatment to help them. The investigators failed to demonstrate that the information
they sought was in the children’s best interest or "unprocurable by other means”—as required by
the Nuremberg Code (1947).
Case 5: Antidepressants: concealed risks, false claims, hazardous experiments
Since their introduction, antidepressant drugs of the selective serotonin reuptake
inhibitors (SSRIs) class have generated controversy. Case reports linked these drugs to severe
adverse effects “ranging from restlessness, extreme agitation and self-destructive impulses and
behaviors” (Anderson 1995, p. 48). Industry and institutional psychiatry vehemently denied the
drugs’ hazards for some patients, dismissing reports of suicidal behavior in adults (Teicher 1991;
Creaney 1991;Wirshing 1992) and children (King 1991) as anecdotal. They proclaimed these
drugs to be safe and effective with few side effects (Cowley 1990), and declared the suicides a
consequence of depression not the drugs. Aggressive marketing of these “magic bullets” has
generated $12 billion in SSRI sales in 2002, a 73% increase since 1998 (Dobbs 2003).
However, recent independent analyses of unpublished company data submitted to the
FDA during the licensure process that had been concealed from published reports (Bosley 2003)

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contradict those efficacy claims. In controlled clinical trials SSRIs failed to demonstrate greater
efficacy than placebo or older antidepressants (Geddes 2000). The high 33% to 85% drop-out
rate during short-term trials suggests that subjects experienced intolerable adverse effects (Healy
2003). The unpublished evidence confirms earlier case reports of drug-induced severe adverse
effects in adults and children (Healy 1997; Healy 2000; Moore 1997; Pfizer 1997). Some
suffered prolonged severe drug withdrawal symptoms (Black 2000), others became violent or
driven to suicidal acts (Boseley 2003; GSK 2003; Healy 1994; Khan 2000; Kirsch 2002;
Sherman 2002; UK 2003;)—even patients who had not previously shown suicidal tendencies
(Healy 2000).
Critics who analyzed the clinical trial data submitted to the FDA concluded that SSRIs
are “among the most toxic drugs in widespread use as measured by the number, variety, and
severity of adverse effects.” (Moore 1997 online) Indeed, a recently published study from Yale
suggests that up to 8% of patients admitted to psychiatric emergency facilities may suffer from
SSRI induced mania or psychosis (Preda 2001). But the public and physicians have been grossly
misled to believe that SSRIs are completely safe and effective, leading doctors to prescribe them
widely, not just for depression but also for an array of non-medical “conditions,” such as shyness
(Healy 1997a; Glenmullen 2000). Even irritable babies are prescribed antidepressants (Grinfeld
1998).
Pharmaceutical companies, FDA officials, and the investigators who had access to the
data must have known that clinical trials failed to demonstrate the effectiveness of SSRIs when
compared to placebo. Dr. Robert Temple, director of the Office of Drug Evaluation at the FDA,
acknowledged “the preponderance of negative studies of antidepressants in pediatric
populations” (US FDA 2000). All but one pediatric study resulted in negative findings. That

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much publicized study by Emslie (1997) and colleagues, claimed “[f]luoxetine treatment was
superior to placebo in relieving depressive symptoms” (p. 1031). However, the differential
between Prozac and placebo for complete remission was only 8%. Their claim, “side effects, as a
reason for discontinuation, were minimal, affecting only 4 patients who were receiving
fluoxetine…” (p. 1033) doesn’t account for the 37.5% drop out rate. Furthermore, those 4
children (8.3%) suffered “manic symptoms” and “severe rash” (Cohen, in press), not minor
effects.
FDA officials also knew that despite efforts to exclude suicidal patients from clinical
trials, the incidence of suicide preoccupation, attempts, and completion, among patients testing
the drugs occurred with disturbing frequency, far exceeding the incidence in patients on placebo.
Healy (2000) reported that the risk of suicide exists whether the test subjects are depressed or
not—even healthy volunteers became suicidal after taking an SSRI for only 2-3 weeks. Khan
(2000), for example, found that among 19,639 patients tested on seven SSRIs, 34 patients had
committed suicide and 130 attempted suicide. Of these, only two patients who committed suicide
were in the placebo arm, as were 15 of the 130 suicide attempters.
In June 2003, the public learned about concealed evidence from nine pediatric trials of
Paxil (paroxetine) in 1,000 children revealing the drug was of no benefit for depressed children
but posed a two to three-fold increased suicide risk compared to placebo. Public disclosure of
these findings prompted the British government to ban Paxil for use in children under 18 (UK
2003; Bosley 2003), the FDA issued a warning about the potential risk on its website, and
GlaxoSmithKline (2003) Paxil manufacturer, then Wyeth (2003), manufacturer of Effexor
(venflaxamine), issued letters of warning to physicians acknowledging the suicide risk and lack

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of drug efficacy in children. Revelations such as these raise serious doubt about the veracity of
clinical trial reports relating to SSRIs and possibly other psychotropic drugs.
Unpublished reports to the FDA reveal that dose tolerance tests push children’s
endurance, triggering severe adverse events (SAE), including suicidal behavior. A Pfizer (1997)
report about Zoloft (sertraline) “forced titration” tests defined SAEs as “events which were fatal;
life-threatening or potentially life-threatening; resulted in permanent disability; required
hospitalization or prolongation of hospitalization…a drug overdose or suggested significant
hazard to the patient” (p. 27). The report describes a 51-day open label “forced titration” study
in 61 children (aged 6-12 ) and adolescents (aged 13-17) who were recruited to test the
pharmacokinetics of and tolerance to Zoloft after single and multiple doses. Of these 61 children
44 were diagnosed as depressed, and 17 with obsessive-compulsive disorder (OCD). During the
first four weeks of the trial the children’s dose was increased to 200mg—a dose higher than was
tested in adult trials. Pfizer reported: “the mean maximum daily dose of sertraline was
considerably higher in the paediatric studies (185mg) than in the adult OCD studies (148mg)…
due to the design of the paediatric studies.” (p. 31) In healthy adult volunteers a 200mg dose
induced nausea, vomiting, diarrhea, giddiness, restlessness, tremor and lockjaw, producing
marked “deterioration” in their cognitive function and emotional stability (Saletu 1986). The
rationale for exposing children to a higher dose, and hence, to greater risks than adults remains
unclear.
Pfizer (1996) reported to the FDA that among the group of 44 depressed children testing
Zoloft, 4 attempted suicide – a rate of 9%. Among these, an eight-year-old boy (patient #4) who
had been in the trial for 36 days: “was hospitalized for a suicide gesture, and dropped from the
study. The patient #4 mutilated himself by cutting his feet with a razor blade and tying a tie

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around his neck” (p. 23 Table 1) Pfizer’s report acknowledges no previous history of self-
mutilation or suicidality, “the event was attributed to study drug by the investigator” (p. 23). The
published report declared: “despite forced titration to 200 mg/day… sertraline was well tolerated
by both child and adolescent patients.” (Alderman 1998, p. 393).
The rationale given for testing psychotropic drugs on children is their widespread over-
prescription by physicians, without evidence of their safety in children. Arguably, the solution
for over-prescription is not to expose additional children to the very drugs that pose risk of
harm—especially in the absence of credible evidence demonstrating beneficial effects greater
than placebo. In fact, compelling clinical evidence from a recent chart review of Massachusetts
General Hospital clinics shows that 74% of children prescribed any one of the popular SSRIs had
suffered an adverse effect. Dr. Timothy Wilens (2003) and colleagues found that 22% of children
had suffered severe psychiatric adverse effects (PAE), and 44% suffered an additional PAE when
re-exposed to the drug after withdrawal. Even those who promote these drugs acknowledge the
absence of outcome data following long-term exposure. The possibility that antidepressant drugs
produce permanent neurological damage with long-term use is especially troubling as regards
children whose brains are still developing (Coyle 1997; 2000).
A front-page article in the New York Times on August 7, 2003, reported that the safety of
SSRIs was once again being debated, and that 7 out of the 10 experts who in 1991 served on
FDA’s advisory panel that cleared SSRIs of triggering suicide, said they would now reconsider
their decision (Harris 2003). Dr. Robert Friedman (2003), director of the psychopharmacology
clinic at Cornell University conceded that drug company manipulation resulted in “publication
bias” which “has a profound impact on medical practice” giving doctors a “distorted impression

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about the safety and efficacy of new medications.” Friedman further acknowledged,
“Government approval is not a guarantee of safety.”
Conclusion and Recommendations
The weight of evidence supports the thesis of this paper. Unchecked pharmaceutical
industry influence has undermined the integrity of academic medical research, the integrity of
FDA’s drug review and approval process, and the integrity of the scientific literature upon which
clinicians have relied to guide their practice. Prior to FDAMA children were protected under
federal regulations prohibiting their recruitment for experiments that were not in their best
interest. The financial incentives of FDAMA have generated an explosion of pediatric clinical
drug trials, but the direct beneficiaries of these experiments are not the children who served as
human subjects. Child subjects are often "risks bearers" rather than beneficiaries. Undoubtedly,
those who benefit are drug manufacturers and the research stakeholders whom they finance.
The following recommendations would protect healthy and disabled children from exposure
to unjustifiable risk of harm in experiments that jeopardize their best interest:
1) Restrict the use of children in medical experiments involving greater than minimal risk
unless the potential benefit for them or their condition justifies the risk Thus, only children
whose currently diagnosed medical conditions could be helped should be recruited to test
drugs or other medical devices or procedures.
2) Establish independent Children Protection Committees to monitor recruitment, assess the
reasonableness of their parent’s permission, assess the adequacy of disclosure in the
informed consent process, and monitor a child’s continued willingness to participate,
thereby ensuring that child subjects are not exploited.

20
3) Identify specific scientifically demonstrable risk factors as likely predictors of disease in the
children being recruited, assuring that current "best medical practice" standards of treatment
will be compared to any new or experimental treatment.
4) Prohibit conflicts of interest, such as recruitment fees to physicians or parents.
5) Establish a registry of all pediatric clinical trials requiring mandatory reporting of serious
adverse effects, and mandate long-term monitoring for adverse effects.
6) Ensure that selection of child subjects does not place an unfair burden on disadvantaged
families who don’t have healthcare coverage.
7) Impose stiff penalties when foreseeable risks have not been disclosed or informed consent
requirements have been violated.
8) Assure every child participant protection by no-fault insurance coverage against possible harm
arising from, or in the course of research.
9) Prohibit use of children in trials of treatments not intended for children.
10) Require licensure of researchers who conduct research on human subjects, including
specialization in pediatric research to ensure their proficiency in both medical ethics and
standards of medical practice.
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