The impact of the Food and Drug Administration Modernization Act on the recruitment of children for research

Abstract

This article argues that contrary to the claims made by research stakeholders in industry, academia and government, the shift in public policy since the enactment of the Food and Drug Administration Modernization Act (FDAMA) of 1997 and its financial incentives to industry to test drugs on children, has had a deleterious impact on children's dignity, health and welfare. Those lucrative incentives offered an opportunity to accelerate the pace of FDA approval for pediatric drug marketing. FDAMA resulted in a radical shift in federal policy to accommodate an expansion of pediatric trials. Children who are precluded from exercising a human adult's right to informed consent to research are increasingly sought as test subjects even when the trials offer no potential benefit for them. Prior to FDAMA children were protected under federal regulations that prohibited their recruitment for experiments that were not in their best interest. This article discusses eight cases and controversies demonstrating that children have been subjected to experiments that exposed them to pain, discomfort, and serious risks of harm. Babies have died testing a lethal heartburn drug; children have been subjected to "forced dose titration" in antidepressant drug trials that resulted in several suicide attempts. Toddlers are currently being subjected to methylphenidate dose tolerance tests without evidence of any pathological condition. Healthy teenagers are being exposed to antipsychotic drugs known to induce severe pathological side effects in speculative "schizophrenia prevention" experiments.

Full text

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
THE IMPACT OF THE FDA MODERNIZATION ACT
ON THE RECRUITMENT OF CHILDREN FOR RESEARCH
Vera Hassner Sharav
Abstract
This paper argues that contrary to the claims made by the research stakeholders in industry,
academia and government, the shift in public policy since the enactment of the FDA
Modernization Act (FDAMA) of 1997 and its financial incentives to industry to test drugs on
children, has had a deleterious impact on children’s dignity, health and welfare. Those lucrative
incentives offered an opportunity to accelerate the pace of FDA approval for pediatric drug
marketing. FDAMA resulted in a radical shift in federal policy to accommodate an expansion of
pediatric trials. Children who are precluded from exercising a human adult’s right to informed
consent to research are increasingly sought as test subjects even when the trials offer no potential
benefit for them. Prior to FDAMA children were protected under federal regulations that
prohibited their recruitment for experiments that were not in their best interest. But as the cases
described will demonstrate children have been subjected to experiments that exposed them to
pain, discomfort, and serious risks of harm—including suicide. Babies have died testing a lethal
heartburn drug; children have been subjected to “forced dose titration” in antidepressant drug
trials that resulted in several suicide attempts. Toddlers are currently being subjected to Ritalin
dose tolerance tests without evidence of any pathological condition. Healthy teenagers are being
exposed to antipsychotic drugs known to induce severe pathological side effects in speculative
“schizophrenia prevention” experiments.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
The ubiquitous influence of the pharmaceutical industry on healthcare, academia and
government oversight agencies has transformed the culture of medical research (Angell, 2000).
Children, who cannot exercise free will, have been particularly affected adversely. This paper
examines the impact of corporate business ethics on research as well as the culture of research in
which children have been subjected to pain and exposed to risks of potential long-term harm.
A public policy shift has accelerated the pace of drug testing and expanded the use of children
as research subjects. The Prescription Drug User Fee Act (PDUFA, see U.S. Public Law 102-571,
21 USC 301) of 1992 speeded up the drug approval process and officially ushered drug company
influence on this process at the United States Food and Drug Administration (FDA) by instituting
company user fees. These fees created a conflict of interest at the FDA. Congress passed the PDUFA
under intense pressure from AIDS activists seeking immediate approval of potentially life-saving but
experimental drugs. The demands of these activists inadvertently presented the pharmaceutical
industry and its allies with an opportunity to "loosen regulatory brakes" (Sharav, 2002; Willman,
2000a) by demanding the same “lenient” and “fast-track” standards for the review of drugs not aimed
at treating “life-threatening illness” (Lurie & Wolfe, 1998; Public Citizen, 2001b; Willman, 1998).
In 1997, the FDA Modernization Act (FDAMA, see U.S. Public Law 105-115, 21 USC
301) expanded the PDUFA’s policy shifts by codifying a number of practices that had become
common at the FDA. According to Public Citizen (2001b), “FDAMA expanded the use of
‘accelerated approval’ mechanisms for drugs for life-threatening conditions and using surrogate
endpoints in clinical trials. It also included a number of mechanisms for speeding FDA review
and changed the legal standard for new drug approval to a single clinical trial (instead of two).”
The law also offered pharmaceutical companies financial incentives to enroll children as research

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
subjects. FDAMA extended the length of a manufacturer’s market exclusivity by six months for
any patented drug or one under development, if the drug was tested on children in controlled
clinical trials. For individual top selling drugs, such an extension can mean revenues of $284
million to $975 million (Zimmerman, 2001)
Prior to FDAMA, children were protected under Federal regulations adopted in 1983
(United States Code of Federal Regulations, 1983), which restricted the recruitment of children
to research that offers them a potential direct benefit. The restriction aimed to protect children,
who cannot volunteer and are vulnerable to exploitation, from undue risks of harm even if
research offers a prospect of direct benefit to the child: “Research involving greater than minimal
risk but presenting the prospect of direct benefit to the individual subjects” is permissible only if
“the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that
presented by available alternative approaches.” If the research involves even a “minor increase”
over minimal risk but does not have a prospect of direct benefit to the child, the regulations
restrict such research to that which “is likely to yield” knowledge that is of “vital importance” for
understanding or amelioration of the child’s disorder or condition (45 CFR 46.407 *.406* )
Unfortunately, regulations do not have the force of law. Unlike laboratory animals
(protected by law since 1966), children subjected to research are not protected by an independent
oversight system. No one maintains a record of the number or nature of clinical trials or of the
subjects’ disposition following research (Institute of Medicine, 2002). Children are now at the
mercy of local institutional review boards that, as will be shown in this paper, may approve
experiments that put children’s health and welfare at risk of harm. Furthermore, researchers who
have violated existing regulations have not been held accountable.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
FDAMA was enacted following intense lobbying by biomedical industry stakeholders—
including industry-supported children’s “advocacy” organizations (see Public Citizen, 2001b)
who claimed that financial incentives were necessary to prod drug companies to conduct
pediatric trials that would provide data to legitimize the use of drugs in children. It was argued
that clinical trials are needed to provide physicians with safety and efficacy information, and that
the absence of FDA-approved, pediatric dose information put children at risk of adverse drug
reactions from wrong doses (Greeley, 2002) Congress accepted these claims at face value,
although a reliable, widely used guide to inform pediatricians about pediatric dosing, the Harriet
Lane Handbook (Siberry, Iannone, & Childs, 1996), has long existed. Furthermore, FDAMA
failed to provide safeguards against child exploitation or ensure that patent exclusivity incentives
would lead to studies of vital medical importance for children. Instead, the (brand name)
pharmaceutical industry and its lobbying arm, the Pharmaceutical Research and Manufacturers
Association of America (PhRMA) have been accused of distorting the public health goal of
FDAMA by demanding patent exclusivity “for virtually any study in pediatric subjects, no
matter how trivial the study design, and regardless of the medical significance or utility of the
data obtained” (Teva Pharmaceuticals, 2000). Congress also failed to conduct an impact
assessment of the new law. According to Dembner (2001a), the number of young subjects
enrolled in clinical trials in the United States swelled from 16,000 in 1997 to 45,000 in 2001.
FDAMA offered the research enterprise opportunities for increased profits and
expansion. In 1999, the National Institute of Child Health and Human Development expanded
the network of pediatric pharmacology research units at key academic institutions from 7 to 13.
Steinbrook (2002) reported that the network conducted many of the studies related to pediatric
exclusivity, and that additional funding is planned for the units. These lucrative partnerships

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
between industry and academia facilitate a utilitarian goal—the rapid development and
marketing of new drugs—but, arguably, have precipitated morally dubious policy changes.
Public health officials set in motion a strategy for loosening federal restrictions that had been
adopted to protect children from exploitation. FDA (1998) adopted the “Pediatric Rule”
requiring that “new drugs and biologic products be studied in children at the same time, or soon
after approval [for use in adults]. The final rule establishes a presumption that all new drugs and
biologics will be studied in pediatric patients” (p. 66634).
1
The National Institutes of Health
(1998) issued new policy guidelines for grant applications stating that children “must be included
in all human subjects research, conducted or supported by the NIH unless there are scientific and
ethical reasons not to include them.” In sum, whereas the goal of the 1983 regulations had been
to minimize the exposure of children to the risks of experimental research, the goals of recent
changes have been to remove those barriers to child exploitation.
The FDA (1999) acknowledged that prior to FDAMA the use of children as subjects in
Phase I drug studies “had been primarily limited to life threatening diseases and children who
had the disease” in question. FDA and the Department of Health and Human Services (DHHS)
convened advisory panels to facilitate the recruitment of children for drug trials. The panels
obliged by “reinterpreting” federal prohibitions protecting children from experiments involving
greater than minimal risk when no potential direct benefit to them or their condition exists. These
advisory committees sanctioned the recruitment of healthy children to be used as "risk-bearing
normal control subjects" (DHHS, 2001; Sharav, 2001). The rationale given was that even
children free of a particular medical condition may be “at risk” of suffering from the condition
and may therefore be recruited and subjected to research risks to stave off the possible future
condition. FDA acknowledged that the post-FDAMA policy change “led to an increasing

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
number of proposals for studies of safety and pharmacokinetics, including those in children who
do not have the condition for which the drug is intended” (Murphy, 2001). Since the adoption of
the "Pediatric Rule," the FDA received 229 proposals from drug manufacturers and issued 191
written requests for pediatric studies (Murphy, 2001). According to Dr. Rosemary Roberts
(2002) FDA’s Deputy Director of Pediatric Drug Evaluation, there were only six “significant”
label changes for dosing or safety. In 2002 Congress extended the financial incentive provision
of FDAMA for five years, and enacted measures “to stimulate pediatric studies of drugs’ under
development and for drugs no longer patented. (Biotechnology Industry Organization, 2003)
Zimmerman (2001) estimated expected additional revenues to drug companies resulting from the
marketing of approved drugs for children to total $6 billion annually.
The financial incentive may in part explain how FDAMA accelerated the pace of
bringing new drugs into the pediatric market even before their safety (i.e., the rate of adverse
effects) in adults was known. In effect, the new policy targeting children and infants as test
subjects in clinical trials was advanced with little debate by those who see nothing wrong with
exposing a few young human beings to risks of harm for the claimed greater good of society. The
1983 regulations were adopted after a vigorous debate regarding society’s moral obligation
toward children who cannot give a mature and informed consent. Ethicist Ramsey argued that
this moral obligation overarches the obligation of scientific exploration: “Children should not be
made the subjects of medical experimentation unless, other remedies having failed to relieve
their grave illness, it is reasonable to believe that the administration of a drug as yet untested or
insufficiently tested on human beings … may further the patient’s own recovery” (cited in
Glantz, 1998, p. 234, italics in original). Rather than confront that moral question, some have
claimed that it is safer to medicate a child under controlled research conditions than under a

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
physician's care. However, in research studies individual needs typically give way to
standardized protocols, including fixed doses. Since doses often need to be individualized,
clinical observation may be superior in this regard than controlled trials (Healy, 2002a). An
examination of the new policy’s impact suggests that children have been actually put at increased
risks of receiving inappropriate or harmful drugs both in clinical practice and research. And it
contradicts the advice of FDA’s own commissioner, who cautioned against taking a new drug
until its adverse effects are known, at least one year after it has been on the market (Neergaard,
2000a).
To facilitate pediatric research of greater than minimal risk and no direct benefit to
subjects constituted a major policy change, which was effected without an open regulatory
review process. Instead, the National Institutes of Health (1998) and FDA (1998, 1999) set about
to “reinterpret” federal restrictions on the use of children by convening advisory committees,
issuing guidelines, and publishing articles arguing to broaden the interpretation of regulatory
language. They argued against being held to a consistent standard for the assessment of “minimal
risk” and “minor increase over minimal risk.” Vitiello, Jensen and Hoagwood (1999), leading
child psychiatrists from the National Institute of Mental Health (NIMH), argued for a relativist
ethics approach, stating that “the interpretation [of minimal risk] varies across clinical context,
institutional settings, and IRBs” (p. 1046). They proposed that in nontherapeutic research—
where no potential benefit for the child subject exists—the determination of risk level should be
the ratio between risk to the subject and “the scientific value of the project” (p. 1048).
An equivocating consensus statement by FDA’s pediatric Ethics Working Group (FDA,
2000a) opened the gate for easier access to children. The advisory panel first recognized that, “In
general, pediatric studies should be conducted in subjects who may benefit from participation in

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
the trial. Usually this implies the subject has or is susceptible to the disease under study.” It then
indicated that it chose to utilize “a broad definition of potential benefit,” citing the example of
the common ear infection. The panel argued that since most children will at some time get an ear
infection, then every child is “at risk,” and, therefore, every child may potentially derive a
benefit from testing a new treatment for ear infection. This reasoning allows any child to be used
as a subject by speculating about a possible future benefit. Vitiello et al. (1999) wrote that “a
particular category of potential research subjects is that of children who do not present with
disorders or psychopathology but are considered at risk for mental illness” (p. 1046). At FDA’s
pediatric subcommittee deliberations (November 5, 1999), it was suggested that the regulatory
definition of “minimal risk” (“probability and magnitude of harm encountered in everyday life”)
does not exclude death: “a risk of everyday life includes death.” It would appear, therefore, that
at least some members on FDA’s Pediatric Advisory Subcommittee consider death “minimal
risk” for research purposes.
The stunning shift in federal policy following FDAMA demonstrates how existing
regulations can be bent. This utilitarian approach absolves the research community from the
time-honored medical injunction—“First, do no harm”—and casts aside the “best interest of the
child” standard, as well as the need to demonstrate a favorable risk/benefit ratio before
permitting the use of children in painful experiments. Additionally, Vitiello et al.’s own
acknowledgement casts doubt about whether psychiatry has even met the “scientific value”
standard: “thus far, research on the biological substrates of mental illness has yielded relatively
little specific information on the pathogenesis of psychiatric disorders” (p. 1045).
Research stakeholders, government officials, politicians, and the editors of the New York
Times (“The Need to Test,” 2002) have claimed that by conducting clinical trials on children, the

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
benefits to be gained for all children outweigh the risks to the subjects. However, those making
the claim may not be free from financial conflicts of interest. Pharmaceutical industry influence
is not marginal or isolated, it is ubiquitous, affecting all facets of biomedical research. Academia,
government, professional journals, and advocacy organizations are all under its influence
(Angell, 2000; Public Citizen, 2001a), so too, are bioethicists and the media (Elliot 2001; Sharav,
2001). Those who make claims that promote recruitment of children for experiments involving
risks of harm and pain for the benefit of all children do not volunteer their own children or
grandchildren. When the argument was made in a court of law in a case involving research on
lead poisoning, it was unequivocally rejected by Maryland’s highest court (Grimes v. Kennedy
Krieger, 2001, see discussion ahead).
As will become apparent from the case descriptions that follow, following FDAMA
many children have been subjected to experiments that did not serve their best interest (Stolberg,
2001). Children have been subjected to a lethal heartburn drug and a plethora of psychoactive
drugs leading some to serious self-destructive behavior (King et al, 1991) Young children have
even been subjected to painful spinal taps and the attendant risks involved, without therapeutic
intent (e.g., Mittleman et al, 1997; Castellanos et al, 2002).
Case 1: Testing a Heartburn Drug in Babies
In 1999, nine-month old Gage Stevens was recruited to test Propulsid (cisapride), a
heartburn drug approved by the FDA’s advisory panel in 1993 despite clinical trial evidence
showing that Propulsid prolonged the QT interval (a potentially fatal heart rate irregularity).
FDA's advisory panel had recommended approval of Propulsid without consulting with the
agency’s own cardiology division (Willman, 2000b). In 1996 the FDA had informed the drug’s

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
manufacturer that Propulsid was “not approvable” for children (Neergaard, 2000b), and in 1997
the director of the FDA's gastrointestinal drugs division acknowledged that “at least” three
children had died after being given the drug (Willman, 2000b). Yet, in 1998, FDA approved the
recruitment of 100 babies for clinical trials of Propulsid and apparently allowed these trials to
continue despite knowledge of the drug's deadly effects (Mazo, 2000). The babies had been born
with gastroesophageal reflux, a minor condition that resolves before one year of age.
In the year that Gage was recruited, Propulsid sales reached $950 million. “As of
December 31, 1999,” according to the FDA (2000c), “there were 341 cases of cardiac arrythmia
and 80 deaths reported.” Gage died of cardiac arrhythmia — as had six-month-old Chase Brown
the year before. By the time Propulsid was taken off the market in 2000, 19 children had died. In
an editorial, the Pittsburgh Post-Gazette asked whether — to facilitate recruitment of children —
the research consent forms had falsely claimed that the FDA had approved the drug for use in
children (Full disclosure, 2000). After his death, Gage’s parents were quoted as saying, “Little
did we know that Gage was basically a guinea pig… They never told us … there had been
deaths” (Mazo, 2000). The final blow was delivered when the parents learned from the autopsy
report that their baby’s esophagus “failed to show signs of significant inflammation or other
hallmarks of gastroesophageal reflux” (Spice, 2000). In other words, the baby did not appear to
have the condition for which he was entered as a subject into a clinical trial.
A Boston Globe investigative series by Alice Dembner (2001a, 2001b, 2001c) has
revealed how ethical standards have been violated and children have suffered and died in clinical
trials. For example, some children were induced with Toys 'R Us gift certificates to assume risks
in drug trials not in their own best interests, while some parents in need of money have been

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
offered as much as $1,000 to enroll their children in drug experiments (see also Jetter, 2000).
Physicians violated the 1998 Code of Ethics of the American Medical Association by accepting
$5,000 referral fees for recruiting the children.
2
Dembner (2001a) reported that between 1994
and 2001, at least eight children died in medical experiments and hundreds suffered harmful
effects. She suggested that, given the tendency of researchers not to report adverse events in
clinical trials and given the threefold increase in the number of child research subjects in four
years, “there is strong reason to believe that deaths and injuries in research involving children are
more widespread” than available statistics would indicate. (Dembner, 2001a; Sabo, 2001) In
their review of 561 pediatric research studies published in five medical journals, Bauchner and
Sharfstein (2001) found that 40% failed to report whether the procedures “were in accordance
with the ethical standards of the responsible committee on human experimentation.” The authors
concluded: “Unless we enhance our system of safeguards, an unethical study could be published.
While the primary responsibility for assuring ethical conduct of research rests with investigators,
peer review journals should be more active in protecting human subjects” (p. 319).
PSYCHOACTIVE DRUGS: ARE THE RISKS FOR CHILDREN JUSTIFIED?
Seven of eight cases and controversies discussed in this paper pertain to psychoactive drug tests
because of the inherent ethical and diagnostic problems involved and their explosive rise in
pediatric use in clinical practice and research. (Diller, 2000; Grinfeld, 1998; Rushton, 2000;
Vitiello, 2001; Voelker, 1999; Zito, Safer, dosReis, Gardner, Boles, & Lynch, 2000). Serious
safety concerns have been raised about psychotropic drugs and the trials testing them. A body of
evidence reveals that psychiatric drugs may have significant adverse neurological and
physiological effects, including brain damage with long-term use (critical reviews by Glenmulen,

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
2000; Healy, 1997; Whitaker, 2002). These concerns are magnified when children are
experimental subjects.
Before a physician can legitimately prescribe a drug to treat or prevent a medical
condition, four methodological issues must be addressed:
1. whether the diagnosis is valid and the instruments used are objective;
2. whether minor or transient symptoms predict the risk of future full-blown pathology;
3. whether drugs used to treat a manifest condition, such as “schizophrenia,” are most
appropriate to prevent the condition; and
4. whether the risk/ benefit ratio favors the drug treatment.
Several problems exist with prescribing (or testing) perception- and behavior-altering drugs for
children. There is the absence of objective criteria for diagnosing children with pathological
behavioral problems. Psychotropic drugs are prescribed for adults and children who have been
led to believe, without proof, that they have a “chemical imbalance” in their brain (e.g., Breggin
& Cohen, 1999; Kaiser 1996; Moore 1998; Valenstein, 1998, p. 96). Demonstrable evidence
exists linking some psychotropics to severe adverse effects. Researchers know, but treating
clinicians and the public often do not, that some psychotropics, such as neuroleptics, also
produce profound, long-lasting cognitive and functional alterations in the brain, and that the
drugs may have in fact worsened patients’ prognosis for recovery (Bowers & Swigar, 1988;
Hegarty, Baldessarini, Tohen, Waternaux, & Oepen, 1994; VanPutten & Marder, 1987;
Whitaker, 2002). Whether used illegally or by prescription, the mechanisms by which all
psychoactive drugs work are identical (Konradi, Leveque, & Hyman, 1996). In a much cited
article, Hyman and Nestler (1996) stated that “chronic administration of psychoactive drugs
creates perturbations in neurotransmitter function” which “cause molecular and cellular changes

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
in neural function” (p. 151). They explained that repeated “perturbations” (i.e., chronic use of
psychoactive drugs) “usurp normal homeostatic mechanisms within neurons” (i.e., interfere with
normal brain function) “thereby producing adaptations that lead to substantial and long-lasting
alterations in neural function" (p. 153). Hyman and Nestler noted that these neural adaptations
might not be beneficial to the organism, citing the possibility that neural adaptation to stimulant
drugs results in addiction.
Case 2: The Attention-Deficit/ Hyperactivity Disorder/ Methylphenidate Controversy
In 1998, a panel of experts convened by the National Institutes of Health failed to reach a
consensus about either the diagnostic criteria or the best treatment of ADHD. Even mainstream
critics are alarmed about evidence of misuse and overuse of psychoactive drugs in children
(Coyle, 2000; Diller, 2000). Critics point to the absence of any objective diagnosis to justify the
risks (Baughman, 2000; Carey, 2000, 2002) and are concerned about indicators pointing to long-
term harm related to chronic use of psychoactive drugs in children (Breggin & Breggin, 1994;
Diller, 1998; Coyle, 2000; Caser Reports, 2002). It is unclear why NIMH has initiated few, if
any, retrospective outcome surveys to determine whether psychoactive drugs have done more
harm than good to the generation of children to whom they have been widely prescribed.
Proponents of psychostimulant drug treatment for ADHD—among them, members of
NIMH and its Research Unit on Pediatric Psychopharmacology (RUPP), the American
Psychiatric Association (APA), and the American Academy of Child and Adolescent Psychiatry
(AACAP)—seem undeterred by a growing body of evidence suggesting the possibility of long-
term harm. Hyman and Nestler’s (1996) laboratory findings about the psychostimulants’ link to
addiction in animals are backed up by evidence gathered by the Drug Enforcement Agency

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
(DEA, 1995; 2000) and a 26-year follow-up study of 492 children in the San Francisco Bay area,
half of whom had been prescribed Ritalin as children, half did not (Lambert, 1998;; Lambert &
Hartsough, 1998). Those who had been exposed to Ritalin as children were higher users of both
tobacco (40% compared to 19%) and cocaine (21% compared to 10%). Furthermore, Volkow et
al. (1995) found that methylphenidate acts like cocaine but remains in the brain longer. Vastag
(2001) reported that Volkow’s team was startled by a new finding: "…instead of being a less
potent transport inhibitor than cocaine, methylphenidate was more potent…the data clearly show
that the notion that Ritalin is a weak stimulant is completely incorrect” (online) If Ritalin is more
potent than cocaine, and the ADHD diagnosis has not been validated, one must ask what is the
justification for exposing millions of children to a drug has the potential to result in addiction,
and whose long-term effects are uncharted.
Influential psychopharmacologists such as Biederman and Spencer (2000) claim that
“ADHD is one of the best researched disorders in medicine; in fact, the overall data on its
validity are far more compelling than for many other medical conditions” (p. 77). However, the
American Academy of Pediatrics’ ADHD clinical practice guideline (AAP, 2000), published at
the height of controversy about the overprescribing psychoactive drugs for behavioral problems,
shows that the claim is unfounded. The guideline attempted to legitimize the ADHD diagnosis
while acknowledging the absence of any objective verifiable criteria to support it. AAP claimed
that a “consensus” exists about the DSM-IV criteria, but on the same page acknowledged that
these criteria "remain a consensus without clear empirical data supporting the number of items
required for the diagnosis” and “remain subjective and may be interpreted differently by
different observers” (p. 1163). The guideline recognized that “the questions on which [ADHD]
rating scales are based are subjective and subject to bias" (p. 1164). AAP also acknowledged that

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
current ADHD criteria “do not take into account gender differences or developmental variations
in behavior,” (p.1163) and that “symptoms may not be apparent in a structured clinical setting,”
and may be bound up with “the demands and distraction of the home and school" (p.1160).
Finally, the AAP guideline acknowledged that "brain imaging studies and
electroencephalography do not show reliable differences between children with ADHD and
controls" (p.1167). Nevertheless, AAP endorsed an ADHD diagnosis in children aged 6 to 12
years on the admittedly subjective basis of the DSM-IV criteria and reports (from parents and
teachers) of “inattention,” “hyperactivity,” “academic underachievement,” or “behavior
problems.”
In addition, the Agency for Healthcare Research and Quality (1999) reviewed 78
randomized controlled, peer reviewed, published studies of the drug treatment of ADHD. It
found that in 87% of the studies, the number of dropouts and withdrawals and the reasons for
such withdrawals were not described, neither were the long-term effects and severity of adverse
effects: “overall, numerous deficiencies in the reporting of available randomized controlled trials
limit the assessment of their validity, relevance, precision, and, therefore, their clinical
application. Most studies did not clearly describe clinically important information such as the
primary outcomes of interest” (pp. 4-5). The reviewers could not conduct a comparative analysis
of the findings because of “the low quality of reporting and the large number and heterogeneity
of outcome measures and tests used in the studies.” They reported that these scientifically flawed
studies “show a trend to general improvement over time regardless of treatment…Ritalin appears
to reduce behavior problems in ADHD children as long as it is taken…” (pp. 4-5).
Case 3: The Multimodal Treatment of ADHD (MTA) Study

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
The MTA Cooperative Group (1999) study has been hailed by those who promote psychotropic
drugs for children as “a landmark in the history of treatment research in child psychopathology”
(Barkley, 2000, p. 595). But others are unconvinced about the justification of using
psychostimulants for children whose behavior may be within the range of normalcy (Carey,
2002) and criticize the study for bias and lack of scientific rigor (Breggin, 2000; Leo, 2002).
The NIMH-sponsored study was conducted over a period of 14 months at 10 research
centers on 579 children, aged 7 to 10 years, selected from 4,541 children who were screened for
participation in the experiment. The study included four treatment regimens to which children
were randomly assigned: (1) medication alone, (2) combined medication and behavioral therapy,
(3) behavioral therapy alone, or (4) standard community care which included psychoactive drugs.
The purpose of the study was to find the most effective long-term treatment for ADHD.
However, no long-term follow-up was planned. Parents and teachers rated the children’s
behavior as improved on groups 1 and 2, but blinded classroom observers found no difference
among the four intervention groups (MTA, 1999a, table 5, pp. 1082-1083). As in previous
studies, the children’s academic performance did not improve (pp 1080-1081). Parents reported
side effects of varied severity in 63.7% of the children (most were “mild,” p. 1073), but no
trained professionals observed or evaluated either the children’s symptoms or adverse drug
reactions.
The MTA study “findings” are a matter of dispute even among the investigators, who
have focused their reporting mostly on whether drugs alone or a combination of drugs and
behavioral therapy improved children’s behavior.
3
Oddly, one of the key findings of the study
(not accentuated by the original study researchers or ever cited by other psychopharmacologists
who have referred to the original study) was that "more than three fourths [of the] subjects

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
receiving behavioral treatment were successfully maintained without medication throughout the
study” (MTA, 1999a, p. 1083). Instead, advocates for drug intervention claim that the study
demonstrated drug efficacy (Swanson et al., 2001).
Several factors complicate the debate surrounding psychotropic drug experiments such as
the MTA. Investigators who seek to test use of psychoactive drugs in children do not address the
fundamental ethical and scientific questions posed by Baughman (2000), Breggin (2000), Carey
(2002), and Coyle (2000):
1. Are the children and adolescents sick, requiring medical intervention?
2. Are their conditions sufficiently serious and disabling to necessitate
pharmacologic intervention?
3. Are the risks associated with the drugs justified?
4. Do the researchers have financial ties to drug companies, and are their
evaluations unbiased?
Glantz (1998) pointed to another (unacknowledged) factor that interferes with impartial selection
and diagnosis of test subjects: "Obviously, if it's the researchers doing the diagnosis, it is in their
interest to diagnose kids with ADHD because they need them for the study" (cited in Montero,
2001).
A survey by Angold, Erkanli, Egger, and Costello (2000) of 1,422 school children found
that 7.3% had been prescribed Ritalin, although only 3.4% had been diagnosed with ADHD.
Even more alarming, Zito and colleagues (2000), examined data on more than 20,000 children
aged 2 to 4 and found that between 1991 and 1995 there was a substantial increase in
prescriptions for children of this age group of psychostimulants, antidepressants and clonodine (a
blood pressure drug with sedative effects). A highly critical editorial by Coyle (2000)

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
accompanied the Zito article, in which he raised concerns about the long-term impact of these
drugs on children’s developing brains. These articles generated a national dialogue. (Then) First
Lady Hilary Clinton convened a White House conference in March 2000 to address public
concerns about inappropriate prescription of psychoactive drugs for children. Hyman asked,
"How can we tolerate a situation in which drugs are prescribed to an increasing number of
preschoolers without safety and efficacy data?" (cited in Huget, 2001). The chairman of the
Judiciary Committee of the House of Representatives called for a federal investigation (Martin,
2000), and several class action lawsuits were filed. However, the White House conference was
dominated by proponents of psychoactive drugs for children. The conference generated no call
for retrospective follow-up studies that would have involved no added risks for children and
might have provided much-needed details for rational decision-making. Nor did conference
participants call for any curbs on prescribing psychoactive drugs for children. Instead what
followed was an aggressive campaign for new initiatives to test psychotropic drugs on ever-
younger children. The deliberations of other high level conferences, and the reports that
followed, were “informed” by powerful psychoactive drug advocates whose work is supported
by pharmaceutical companies. Among those who control the NIMH research agenda in pediatric
psychiatry are its Research Unit on Pediatric Psychopharmacology (RUPP) centers established in
1996-1997 to test the safety and efficacy of drugs. Influential pharmacologic stakeholders
promote the idea that a "mental health crisis"
4
exists, claiming that 14 million (20%) of
American children aged 9 to 17 have a diagnosable mental illness (American Psychiatric
Association, 2002).
By October 2000, NIMH and FDA representatives met to discuss the need to develop
psychopharmaceuticals for preschoolers. Vitiello (2001), NIMH’s director of Child and

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Adolescent Treatment and Preventive Interventions Research Branch, acknowledged to the
assembled that “the ability to formulate a valid and reproducible diagnosis of disorders and
syndromes is a prerequisite for clinical trials” (p. 985). He recognized that this pre-requisite was
lacking by acknowledging (repeatedly) “the diagnostic uncertainty surrounding most
manifestations of psychopathology in early childhood”
(p. 983). He admitted that “very little
research has been done to demonstrate replicability across raters and external validity of these
diagnoses in preschoolers” (p. 986). Therefore, “clinical trials of these agents in preschoolers do
not seem possible given the current uncertainties about diagnostic validity of mood disorders in
children <6 years old” (p. 985). Vitiello acknowledged the impact of FDAMA, affirming that
“pediatric psychopharmacology has recently seen an unprecedented expansion…. NIMH-funded
research for clinical trials in youths has more than doubled in the last few years” (p. 987). We are
arguing here that the sharp rise of psychopharmacologic testing in pediatric research is a
response to two contributing factors: widespread illegitimate prescribing of psychiatric drugs to
children, and the financial incentives of FDAMA.
Case 4: Testing Ritalin in Preschool Children
Despite the explicit recognition by a prominent NIMH researcher that the essential ethical and
scientific pre-requisite to clinical investigation of psychotropics in pre-schoolers was lacking,
NIMH embarked on a radical trial exposing three-year-old children to psychoactive drugs. In
November 2000 NIMH initiated the Preschool ADHD Treatment Study (PATS), a $5 million,
multi-center, pediatric research initiative that will expose 312 children three years of age to
psychostimulant drugs to test the drugs’ safety and long-term effects.
The experiment is
designed to test the children’s tolerance level for methylphenidate at increased doses — from 2.5

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
mg once a day, to 15 mg three times a day. The experiment has proceeded despite a lack of
evidence that the study participants either have any validated medical condition or a
demonstration that benefits of using the study drugs outweigh risks to the participants. Parents
will receive $645 if their child completes the 43 study visits and teachers will receive $340 to fill
out rating forms.
Even the study's principal investigator acknowledged that ADHD is "not a well-defined
psychiatric disorder in this age group" (Marshall, 2000a, p. 1280). Given that permanent harm
may be caused to the central nervous systems of young children recruited to test the drugs, the
experiment would seem to be highly questionable, if not altogether unethical and repugnant.
Those initiating the trials have argued that it is safer to expose children to these drugs under
controlled clinical conditions than to rely on pediatricians and primary care physicians to
prescribe these drugs (essentially) in uncontrolled clinical trials.
5
However, if the children’s
behavior is within the range of normalcy (Carey, 2002), the experiments cannot be classified as
therapeutic, and the risks are not justifiable. Indeed, nontherapeutic experiments that put children
at greater than minimal risk are unapprovable under federal regulatory standards — yet, the
preschool methylphenidate experiment is sponsored by the government.
Hyman has stated: “Without good clinical data, every child who receives this medication
represents an uncontrolled experiment — that is entirely unacceptable” (cited in Marshall, 2000a,
p. 1281). But is it morally acceptable to ask little children to assume risks by testing the safety of
psychoactive drugs they may not need, in order to accumulate “good clinical data?” If that
rationale were endorsed, would our society allow some children to be exposed to (potentially)
deadly products in controlled clinical trials to obtain “scientific” information about how to
protect other children? This very issue was the focus of a recent lawsuit involving a lead

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
abatement experiment in which healthy children were exposed to the risks of lead paint so that
researchers could determine the effectiveness of varying degrees of lead paint abatement. The
academic research establishment—including Johns Hopkins University, the University of
Maryland, the Association of American Medical Colleges (AAMC), and the Association of
American Universities—attempted to intervene, arguing that the research would help all other
children (Brief of amici curiae, 2001). The Maryland Court of Appeals unequivocally rejected
their arguments in a strongly worded, landmark decision that severely criticized researchers and
the institution involved for exposing children to risks for the advancement of science (Grimes, et
al, and Higgins v. Kennedy Krieger Institute, 2001) The Court cited the Nuremberg Code and the
Declaration of Helsinki, proclaiming the primacy of individual rights:
…whatever the interests of the general public in fostering research that might, according
to a researcher’s hypothesis, be for the good of all children, this court’s concern for the
particular child … over-arches all other interests. It is, simply, and we hope, succinctly
put, not in the best interest of any healthy child to be intentionally put in a nontherapeutic
situation where his or her health may be impaired, in order to test methods that may
ultimately benefit all children. (p. 80)
Case 5: Ignoring Risks of Antidepressants
The 1988 launching of Prozac, the first selective serotonin reuptake inhibitor (SSRI)
antidepressant was a watershed in psychotropic drug marketing. It set the stage for countless
upbeat news reports, such as a 1990 cover story in Newsweek—“Prozac: A Breakthrough Drug
for Depression." Prozac and the SSRIs that followed were promoted as safer, more effective,
with significantly milder side effects than the earlier tricyclic antidepressants (TCA), which had

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
been shown to cause serious, for some, life-threatening cardiac effects, especially in children
(Wilens & et al., 1996 Mezzacappa et al., 1998), some of whom died of “sudden death”
(Riddle, Geller, Ryan, 1993; Kutcher, 1997; Swanson, Jones, Krasselt, Denmark, Ratti, 1997;
Varley & McClellan, 1997). The academic literature reflects the unreserved promotional claims
made about SSRIs as a breakthrough, safe treatment for depression and the prevention of suicide,
but also for a wide range of “conditions” such as grief, shyness, social dissatisfactions and
problems in living. The wide application of SSRIs adds to the perception that they are “magic
bullets.” Blind faith seems to have led doctors to prescribe SSRIs without hesitation—even to
infants. Grinfeld (1998) reported that FDA data compiled by an industry research firm indicated
that that although not approved for children, Prozac “was prescribed 349,000 times to pediatric
patients under 16, including 3,000 times to infants under 1 year of age.”
However, SSRIs have been linked to severe adverse behavioral and neurological side
effects. (Healy, 1997) In children, the most common of these effects include increased
restlessness (akathisia), insomnia, excitability, hyperkinetic behavior and impulsiveness (King et
al., 1991; Riddle, Hardin, King, Scahill, & Woolston, 1990). Other serious concerns involve
severe withdrawal syndrome (Black, Shea, Dursun, & Kutcher, 2000) and the possible risk of
brain damage—as found in animals (Kalia, O’Callaghan, Miller, & Kramer, 2000; Rustad,
2000). Indeed, Glenmullen (2000) and Healy (2000) an others have compared the damage of
SSRIs to that caused by antipsychotic medications, concluding that future generations may look
back on the use of antidepressants and other psychiatric drugs as “a frightening human
experiment” (see also Goode, 2000).
Recent analyses of reports submitted to the FDA reveal that the resoundingly positive
claims made in published reports are not supported by scientific evidence. In clinical trials,

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
SSRIs were found to be no more effective than either TCAs or placebo (Kirsch, Moore,
Scoboria, & Nicholls, 2002; Moore, 1997). Yet, children continue to be recruited to test
antidepressants despite the risks. The FDA (2000b) acknowledged “the preponderance of
negative studies of antidepressants in pediatric populations.” Indeed, 13 studies comparing the
efficacy of TCAs with placebo in children found no difference in efficacy (Birmaher et al., 1998;
Klein et al., 1998; Kye et al., 1996). Given the negative findings in pediatric trials testing TCAs,
it is reasonable to suspect that SSRIs, which were shown to lack efficacy in adults, will prove no
more effective in children. Indeed, Ambrosini et al (1999) acknowledged that “[r]esults of early
controlled trials of [SSRIs] in pediatric subjects were also discouraging”
Teicher, Cole and Glod (1990) released a fly into the ointment when they first reported
the emergence of “intense, violent and suicidal preoccupation” in six patients after two to seven
weeks of fluoxetine (Prozac) therapy. The authors estimated the risk of developing violent
suicidal preoccupation on Prozac to be 3.5%. But these findings were anathema to the psychiatric
establishment as much as to the pharmaceutical industry: the professional literature is weighted
with reports claiming to disprove Teicher’s findings. In a follow up article, Teicher et al (1993)
reported: “Although antidepressants diminish suicidal ideation in many recipients, about as many
patients experience worsening suicidal ideation on active medication as they do on placebo.
Furthermore, at least as many patients attempted suicide on fluoxetine and tricyclic
antidepressants as on placebo…” (p. 186) Wirshing, van Putten, et al (1991) reported that their
patients with no prior history of suicidal behavior became suicidal during treatment with
fluoxetine, “all described their distress as an intense and novel somatic-emotional state; all
reported an urge to pace that paralleled the intensity of the distress; all experienced suicidal
thoughts at the peak of their restless agitation; and all experienced a remission of their agitation,

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
restlessness, pacing urge, and suicidality after the fluoxetine was discontinued… [l]ike the
akathisia in the neuroleptic-treated schizophrenic population, 'fluoxetine akathisia' can
apparently be associated with suicidal ideation, sometimes of ruminative intensity." Wirshing
1992, p. 580- 581)
Case 6: FDA Data Corroborates a Significant Risk of Suicide
Clinical trial reports submitted by drug manufacturers to the FDA for licensure purposes became
publicly accessible, ironically, through a provision of FDAMA. These documents reveal the
scope and severity of adverse side effects experienced by the subjects in those trials, and they
reveal a significant risk of suicide in psychiatric drug trials. The incidence of suicidal
preoccupation, attempts, and actual suicide in patients testing the new psychotropic drugs occurs
with disturbing frequency, far exceeding the risk for patients on placebo (Kahn, Warner, &
Brown, 2000; Moore, 1997; Whitaker & Kong, 1998; see also Sherman, 2002).
Using antidepressant clinical trial data submitted by manufacturers to the FDA for drug
approval purposes, Khan and colleagues (2000) sought to assess the safety and efficacy of
placebo. These authors found that patients on placebo were actually far less likely to commit
suicide than those testing an investigational drug. Among the 19,639 patients testing 7 SSRI
antidepressants in clinical trials, 34 patients had committed suicide and 130 had attempted
suicide. However, only 2 patients who committed suicide and 15 of the suicide attempters were
in the placebo arms of the trials. Khan, Khan, Leventhal, Krishnan, and Gorman (2002)
presented an expanded analysis of the data to include recently approved antipsychotics as well as
SSRI antidepressants. Between for 1985 to 2000, more than 71,604 patients participated in
clinical trials testing all psychotropic drugs (Sherman, 2002). Khan et al. (2002) found that

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
despite efforts to exclude suicidal patients from clinical trials, the suicide rates were exceedingly
high in clinical trials of short duration. The suicide rate within a year of testing an atypical
antipsychotic was 752 per 100,000 persons and for those testing an SSRI the suicide rate was
718 per 100,000.
These FDA data essentially corroborate the Teicher et al. (1990, 1993) findings and those
reported by Glenmullen (2000) and Healy (2000). Healy (and others) believe that akathisia—
drug induced severe restlessness, anxiety and agitation—is the catalyst that triggers suicidal or
even homicidal behavior in some patients. However, FDA has failed to require disclosure of the
evidence to those most in need of accurate information—clinicians and the public. They have
been mostly kept in the dark about the true risks of psychotropic drugs, except when the press
reports about lawsuits that have brought to light documents that revealed evidence linking SSRIs
to violence and suicidal acts (e.g., Boseley, 1999; Garnett, 2000; Zuckoff, 2000).
Children, more than adults, have endured severe adverse effects in clinical trials.
Although King and colleagues (1991) noted the need to study the incidence of medication-
related agitation, self-injury and emerging suicidal obsession in children taking SSRIs, neither
the NIMH nor the FDA has initiated such study. Neither the drugs’ serious risks nor their lack of
clinical efficacy has dissuaded psychopharmacologists from subjecting ever more children to
clinical trials that expose them to these drugs. Moreover, existing publications of pediatric trials
may present only a partial and biased portrait of the available evidence gathered by investigators.
Klassen and associates (2002) found that more than 40% of medical studies conducted on
children are never published. These authors traced unpublished data that had been presented at
the Society for Pediatric Research and found that invariably such studies had produced negative
findings that raised questions about the safety and/or effectiveness of new drugs. Since many of

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
these drugs were subsequently brought to market, one can argue that parents and clinicians were
misled about the drugs’ actual safety or effectiveness. Some have suggested that this skewing of
the scientific literature is a form of “scientific misconduct” (Picard, 2002). However, as the
following case reveals, even when studies are actually published, authors may not report all the
relevant data, especially concerning serious adverse effects.
Case 7: Forced Dose Titration Tests in Children
Pfizer (1996, 1997) submitted a two-part expert report to the FDA in response to an FDA
memorandum that raised concerns about the “emergence of suicidal ideation, gestures, and
attempts in association with sertraline [Zoloft] use” as a treatment for obsessive-compulsive
disorder (OCD) in children The Pfizer report refers to two completed pediatric trials in the United
States and two extension trials in children aged 6 to 12 years and adolescents aged 13 to 17 years,
diagnosed with either depression or OCD. One study, a 12-week, multi-center, double blind,
placebo controlled trial, recruited 92 children to sertraline and 95 to placebo. Of the latter group,
67 subsequently went onto sertraline in an extension trial. A second open label study lasting 51
days and aiming to explore the pharmacokinetics of and tolerance to sertraline after single and
multiple doses, recruited 61 children, of whom 44 were diagnosed with depressive disorders and
17 with OCD.
Pfizer (1997) reported that during the first four weeks of the second study the children’s
dose was increased to 200mg, higher than in adult trials: “the mean maximum daily dose of
sertraline was considerably higher in the paediatric studies (185mg) than in the adult OCD
studies (148mg).” Pfizer (1997) provided no clear rationale for testing a higher doe in children,
simply stating: “This higher mean maximum daily dose is due to the design of the paediatric

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
studies” (p. 31) It is also unclear why the FDA approved, what Alderman, Wolkow, Chung, and
Johnston, (1998) call the “forced titration” study design, which surely put children under
increased stress. Indeed, in the completed studies, six children on sertraline attempted suicide
and a number of other children became suicidal. Within the group of 44 depressed 4 children,
(9%) attempted suicide. Suicide attempts in the main occurred within a few days of dose
escalation. One of the children who became suicidal was an eight-year-old boy who had been in
the sertraline dose tolerance study for 36 days. Pfizer (1996) states: “Patient was hospitalized for
a suicide gesture, and dropped from the study. The patient mutilated himself by cutting his feet
with a razor blade and tying a tie around his neck. There was no previous history of self-
mutilation or suicidality, although family history was significant for affective disorder (mother,
maternal uncle) and suicide (maternal uncle). The event was attributed to study drug by the
investigator.”(p. 23, Table 1) In the same study a 14-year old who had been receiving 200mg/day
sertraline was hospitalized on the 35
th
day of the study for “a moderate suicide gesture” in which
he ingested “400 mg of sertraline…10 mg of lorazepam and unknown amount of organophospate
insecticide. The suicidal ideation was thought to have resolved within one day and the patient
was not discontinued. The following day the patient ingested 8 g of chloral hydrate.
Nevertheless, the investigator continued the patient in the study five days later, without apparent
further sequelae “(Table 1) Pfizer’s report further notes that this eight year old boy, “had been
treated with methylphenidate 40mg qd for over five years, and this was discontinued
immediately prior o entering the study.” This would indicate that the boy was continuously
prescribed psychoactive drugs since he was nine years old. To what effect, one might ask?
Pfizer (1997) reported 21 “serious adverse events” (SAE) in 16 patients on sertraline
(7.5%) in the OCD studies (p. 28). In the non-OCD studies, there were 11 SAE in 7 patients on

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
sertraline (18.4%). “These included three reports of suicidality, and single reports of malaise,
intentional drug overdose, medical/surgical…aggressive reaction, aggravated depression…” (p.
29) According to Pfizer, “The adverse events most frequently associated with discontinuation
were psychiatric symptoms, most commonly agitation” (p. 21). Children (6 to 12 years) on
sertraline were especially prone to agitation: 15.1% (compared to 1.9% on placebo). Among
adolescents (13 to 17 years), 10.3% became agitated (compared to 2.4% on placebo). Pfizer’s
report acknowledges: “there were no serious adverse events reported in the 95 patients in the
placebo group” (p. 28). Of significance is the fact that these suicide-related events were reported
“spontaneously”—the child-subjects in these trials were not monitored for suicidal
preoccupation. The Pfizer (1996) report acknowledges that “there is minimal information in most
reports about the individual’s history or course of treatment” (p. 13) and “it is well known that
spontaneous reports are not a good indication of the true frequency of events.” (p. 17)
The academic publications stemming from these studies (Alderman et al., 1998; March et
al., 1998) validate Klassen and colleagues’ (2002) findings of skewed reporting, since the
publications fail to report the scope and nature of the SAE suffered by participants in the trials--
only one suicidal event is mentioned. Alderman and colleagues (1998) choose to report only on
adverse events that occurred at a 10% frequency or greater. They report common but less severe
adverse events such as, headache, insomnia, nausea, dizziness, and diarrhea, but fail to report
agitation (15.1%), which several analysts have suggested induces suicidality (Anderson, Segman,
& King, 1995). It is unclear what SAE disclosure criteria, if any, are being followed in these and
other peer reviewed, published clinical trial reports. It is extremely difficult to understand the
investigators’ reluctance to report the actual findings (available in this case only through

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Freedom of Information requests) so that families and clinicians may be alert to the possibility
that SSRIs may increase restlessness, agitation, and/or suicide preoccupation in some patients.
Case 8: Marketing “Schizophrenia Prevention”
The burden of providing an ethical justification for conducting drug trials on children rests with
those who propose the trials. A “schizophrenia prevention” experiment currently being
conducted at Yale University exposes healthy adolescent siblings of individuals diagnosed with
schizophrenia, some as young as 12 years of age, to the effects of a neuroleptic drug, olanzapine
(Zyprexa). The difficulties involved in diagnosing schizophrenia are well known to clinicians
and researchers. As Tsuang, Stone, and Faraone (2002) have acknowledged, “there are no
universal signs of schizophrenia, indicated interventions for this disorder have a somewhat
broader definition than those used in other health fields where clearer signs are available (for
example, borderline hypertension for heart disease” (p. 3 online) Cornblatt, Director of the
division of high-risk studies at Hillside Hospital in New York, a major center for schizophrenia
studies, has further acknowledged that psychiatrists cannot predict who will develop
schizophrenia: "Nobody yet knows what the early symptoms are . . . we don't even clearly know
what the level of risk is; we don't know if 5 percent or 40 percent who are identified with
suspected risk factors are going to become ill" (Goode, 1999, p. F1). Thus, no valid diagnostic or
screening tools exist. The subjects recruited for this study are too young to provide informed
consent or to appreciate the degree of risk to themselves or the scientific uncertainty underlying
the experiment.
Despite the alarming rhetoric by promoters of the “schizophrenia prevention” study, the
incidence rate of schizophrenia in siblings of diagnosed patients is estimated to be between 2%

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
to 6.5% (Kendler & Diehl 1993); 8% (Van Reekum & Cleghorn, 1992); 9% (Gottesman, cited by
Tsuang et al., 2002). Thus, even in the worst scenario, 91% of siblings being recruited for this
experiment will never become ill with schizophrenia if left alone. However, reports about the
experiment in influential newspapers such as the Wall Street Journal and the New York Times
carried headlines that betrayed a commercial pharmaceutical pitch: “New Weapons in the War
Against Schizophrenia” (Tanouye, 1999) and “Doctors Try a Bold Move Against Schizophrenia”
(Goode, 1999).
Olanzapine is known to have produced serious adverse side effects in 22% of adult patients
with schizophrenia in whom it was tested.
6
Among the reported severe adverse effects of the drug
were cardiovascular complications (10% to 15%); acute weight gain (50%); Parkinson-like motor
impairent (11.7%); and unbearable restlessness (akathisia) (7.3%). Since its approval, a review of
FDA’s MedWatch reports by physicians by investigators at FDA’s Center for Drug Evaluation and
Review and Duke University, found a causal association between Zyprexa and diabetes—a condition
that is rare in children and adolescents (Koller, Malozowski, & Doraiswarmy, 2001). The death rate in
Zyprexa pre-marketing clinical trials was higher than in any other neuroleptic drug trial (Healy, 2002;
Whitaker & Kong, 1998). The investigators and the Yale University institutional review board must
have been aware of the body of published evidence showing profound changes in the central nervous
system with demonstrable physical and neurological impairments caused by long-term exposure to
neuroleptics (Gur, Cowell et al, 1998; Gur, Many et al, 1998; Harrison, 1999; Jauss, 1998; Lieberman,
Sheitman, & Kinon, 1997; Madsen, Keidelin, Karle, Esbjerg, & Hemmingsen , 1998). Chakos and
colleagues (1994) demonstrated brain damage in patients exposed to neuroleptics even in the first
psychotic episode. Furthermore, the Australian Adverse Drug Reactions Advisory Committee had
received about olanzapine 18 reports of white blood cell disorders (neutropenia), 15 reports of

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
seizures / convulsions, and 7 reports of neuroleptic malignant syndrome, a potentially fatal adverse
reaction linked to use of all neuroleptic drugs (Public Citizen, 2000; World Health Organization,
2000) A MEDLINE search by this writer identified hundreds of severe, life-threatening adverse
reaction reports in association with olanzapine treatments.
7
In sum, (a) well documented, severe (sometimes irreversible and occasionally fatal) risks
exist in connection with the use of olanzapine, (b) none of the adolescents recruited for the study
met the diagnostic criteria for schizophrenia, (c) by any standard of the time, 85% or more of
these adolescents were not even "at risk" for schizophrenia, (d) few, if any, were likely to derive
any demonstrable personal benefit from the experiment, a requirement under federal regulations ,
(e) several researchers, such as Alex Cowdry, formerly from NIMH, expressed alarm about a
"schizophrenia prevention" experiment on healthy adolescents: "No one knows the long-term
dangers of putting such patients on antipsychotic drugs" (cited in Goode, 1999), and (f) the
adolescents were selected for the study because their siblings had been diagnosed with
schizophrenia and the researchers had hypothesized that the adolescents might be "at risk" for
schizophrenia
8
— a conjecture based on a suspicion. Clearly, no compelling (or even somewhat
reasonable) evidence whatsoever exists to justify the children’s exposure to a drug with such a
high-risk profile. Nevertheless, the FDA approved and the NIMH (partially) funded the
experiment.
Within a year of the Yale University study announcement, the Wall Street Journal
reported that “Radical Study on Schizophrenia May Be Expanded” to a multinational study
targeting 1,500 teenagers, with pharmaceutical companies providing $25 million dollars for the
project (Zimmerman, 2000). A Harvard University team led by Ming T. Tsuang has also
embarked on the “schizophrenia prevention” bandwagon that (in their own words) “is a radical

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
departure from tradition” (Tsuang, and Faraone, 2002c, p. 516) It appears as a far-reaching
strategy to reformulate the diagnosis of schizophrenia by abandoning the DSM IV (American
Psychiatric Association, 1994) diagnostic criteria and broadening the “treatable” patient base
from diagnosed patient to healthy first-degree relatives. Tsuang, Stone, and Faraone (2000)
argue that psychotic symptoms, as the sine qua non of schizophrenia, should be abandoned as a
diagnostic criteria for schizophrenia. Instead, they propose “schizotaxia,” which they
acknowledge is “still an evolving concept” lacking any diagnostic criteria (p. 1047). Tsuang and
colleagues claim that ”schizotaxia” is either a precursor of schizophrenia or a “condition”
without a psychotic component, characterized by neuropsychological deficits and negative
symptoms that need to be validated. They nevertheless argue that “schizotaxia” constitutes a
predisposition to schizophrenia that should be treated. Armed with this new rationale giving
them great latitude, these researchers cast a wider net to initiate pharmacological interventions
for nonpsychotic first-degree relatives of patients diagnosed with schizophrenia. Their drug of
choice is risperidone (Risperdal), an antipsychotic manufactured by Janssen Pharmaceutica.
Although Tsuang and colleagues (2002) estimate that the risk of schizophrenia for first-
degree relatives of diagnosed patients is between 6% and 13%,
9
they claim that “schizotaxia”
afflicts between 20% to 50% of first-degree relatives. That assertion must constitute good news
for the pharmaceutical industry. In August 2002, the Canadian Journal of Psychiatry published
two articles (Faraone, Brown, Glatt, & Tsuang, 2002; Tsuang et al., 2002) and an editorial
(Tsuang & Faraone, 2002b) promoting “schizotaxia” and the “schizotaxia intervention protocol”
for a select sample of first-degree adult relatives of patients with schizophrenia.
However, Tsuang and his Harvard University team are highly critical of Yale
University’s primary prevention studies:

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Prevention studies in children and adolescents have the unintended effect of labeling
them as future schizophrenia patients. This raises the very real possibility of
stigmatization and emotional harm to the subjects and to their families. Moreover, the
type of medications likely to be used in prevention trials may pose greater risks to
children and adolescents than to adults. The use of antipsychotic medications to treat
children, for example, has been limited in part because of concerns about side effects.
(Tsuang et al., 2002, p. 3 online)
These authors further acknowledge that stigmatization and drug-induced pathological changes
“preclude … use [of drugs] without solid evidence of their efficacy but even nonpharmacologic
interventions can be psychologically harmful if their use is not predicated on a solid rationale”
(p. 3 online)
Both the Yale and Harvard experiments are being conducted without evidence (a) of the
diagnostic validity of the condition; (b) of the predictive validity of the screening instruments; (c)
that a conjectured “predisposition” will result in the full-blown condition; (d) that the drugs used
to treat the condition could prevent it; and (e) without evidence that a favorable risk/benefit ratio
to justify the risk of drug-related pathology to the subjects.
CONCLUSION
FDAMA has generated an explosion of pediatric clinical drug trials, but the direct beneficiaries
of the experiments described in this paper are not the children who served as human subjects.
These children are “risks bearers” rather than beneficiaries. Undoubtedly, those who benefit are
drug manufacturers and the research enterprise. The financial incentives under FDAMA include
a six-month patent extension, expanded clinical trials, and early penetration of the pediatric

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
market — not to mention the possibility of expanding the market to undiagnosed relatives of
patients. These financial incentives are enormous. For Eli Lilly and Company, for example, a
six-month patent extension for olanzapine (Zyprexa, with sales at $3.1 billion in 2001) can
generate one and a half billion dollars (Business Summary, 2002). The Yale researchers
discussed above are under contract with Eli Lilly. The experiment has been touted in the national
press as a “bold new move,” a "schizophrenia prevention" study (Goode 1999;Tanouye, 1999).
Following FDAMA, healthy children who do not meet the federal criteria of a
diagnosable disorder or condition to justify any risks they may be exposed to have been recruited
as “risk bearing” subjects to test drugs whose safety is unknown (even in adults), for disorders
they will likely never develop. Murphy (2001) the FDA’s Associate Director of Pediatrics,
alluded to the possibility that children are in danger of being exploited when she stated:
“Children must not become a commodity.” Sadly, children are being reduced as human beings to
serve as means to an end.
1
The Rule was originally issued in 1994, was codified in 1997 and went into effect April 1999 (see
http://www.fda.gov/ohrms/dockets/98fr/120298c.txt
). On Dec. 4, 2000, FDA announced Guidelines for
compliance with Pediatric Rule (see http://www.fda.gov/OHRMS/DOCKETS/98fr/120400c.pdf).
However, on October 15, 2002, a U.S. District Court for District of Columbia struck down FDA's
pediatric rule and enjoined FDA from its enforcement (see
http://www.cei.org/gencon/027,03254.cfm).

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
2
The American Medical Association Code of Medical Ethics, Opinion 6.02, states: "Payment
by or to a physician solely for the referral of a patient is fee splitting and is unethical"
(Available online at the American Academy of Emergency Medicine webpage:
http://www.aaem.org/feesplitting/602.html) .
3
The MTA investigators claimed the study proved that “combined treatment and medication
management treatments were clinically and statistically superior to behavioral treatment and
community care in reducing children’s ADHD symptoms.” But they went on to state that
combined treatment “yielded no significantly greater benefits than medication management
for core ADHD symptoms” (MTA, 1999a, p. 1078).
4
On January 3, 2001, the Surgeon General issued the following statement that captures the
general trend in conferences: "This conference (i.e., the latest one) is one piece of a national
conversation addressing the mental health needs of our Nation's children. The White House
Conference on Mental Health, in June 1999, was the first major public orientation to the
realities of mental illness in the United States. This was followed by the Surgeon General's
Call to Action to Prevent Suicide in July 1999, and the release of a first-ever Surgeon
General's Report on Mental Health in December 1999. This report addressed complex issues
in mental health and included a chapter on the mental health of children. Most recently, in
March 2000, the White House held another meeting specifically addressing the need to
improve the diagnosis and treatment of children with emotional and behavioral conditions.
Following this conference, the National Institute of Mental Health and the Food and Drug
Administration held a meeting in October 2000, focusing on research needed to develop
psychopharmaceuticals for young children" (Surgeon General, 2001).
5
For example, Vitiello (2001) has suggested that the problem of over prescribing
psychoactive drugs to very young children is due to pediatricians and other primary care
physicians who “may have neither the appropriate expertise in developmental
psychopathology nor the time needed to conduct comprehensive psychiatric evaluations” (p.
985).
6
According to FDA data obtained by The Boston Globe under the Freedom of Information
Act, there were 22 deaths, 12 of which were suicides; the drop-out rate during 6-week clinical
trials had been 65%; in an extended (one year) trial, the drop out rate had been 83%.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
7
A MEDLINE search on November 22, 2002 with the terms "Olanzapine and adverse"
elicited 193 initial citations; "and rebound psychosis" (a.k.a., supersensitivity) elicited 280
citations; “Olanzapine and diabetes” elicited 59 citations; and “NMS” elicited 37 citations;
"induced mania" elicited 30 citations; “arrhythmia” elicited 20 citations.
8
The "at risk" rationale had first been invoked by the New York Psychiatric Institute and
Columbia University in a much criticized fenfluramine “challenge” experiment conducted on
6 to 11 year old siblings of incarcerated youth. [Pine, et al., 1997; Montero 1998; Hilts 1998]
9
Tsuang, et al cite a review of 40 European studies between 1920 and 1987 found a 6% risk
for parents; 9% risk for siblings; 5% risk for first degree relatives and half siblings; and 13%
risk for offspring with one parent having schizophrenia. Gottesman II. 1991. Schizophrenia
genesis: the origin of madness. New York: Freeman.
REFERENCES
Agency for Health Care Research & Quality. (1999). Treatment of attention-deficit/hyperactivity
disorder: Summary, evidence Report / Technology assessment number 11. AHQR
Publication No. 00-E005. Retrieved January 15, 2003 from
http://www.ahrq.gov/clinic/adhdsum.htm
Alderman J, Wolkow R, Chung M, Johnston HF. (1998) Sertraline treatment of children and adolescents with
obsessive-compulsive disorder or depression: pharmacokinetics, tolerability, and efficacy. Journal of
the Association of American Child & Adolescent Psychiatry, 37:386-94.
American Academy of Pediatrics. (2000). Clinical practice guideline: Diagnosis and evaluation
of the child with ADHD. Pediatrics, 105, 1158-1170.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
American Psychiatric Association. (1994). Diagnostic and statistical manual of mental
disorders, 4
th
ed. Washington, DC: Author.
American Psychiatric Association-American Academy of Child and Adolescent Psychiatry.
(2002, September 26). Are children being overmedicated? Testimony before the U.S.
House Government Reform Committee on ADHD. Retrieved October 26, 2002 from
http://www.psych.org/pub_pol_adv/testimonys.cfm
Ambrosini, P. J., Wagner K. D., Biederman, J., Glick, I., Tan , C., Elia, J., et al. (1999).
Multicenter open-label sertraline study in adolescent outpatients with major depression.
Journal of the American Academy of Child and Adolescent Psychiatry, 38, 566-572.
Anderson, G. M., Segman, R. H., King, R. A. (1995). Serotonin and suicidality: The impact of
fluoxetine administration. II. Acute neurobiological effects. Israel Journal of Psychiatry
and Related Sciences, 32, 44-50.
Angell, M. (2000). Is academic medicine for sale? New England Journal of Medicine, 342, 1516-
1518.
Angold A, Erkanli A, Egger HL, Costello EJ. 2000. Stimulant treatment for children: a
community perspective. Journal of the American Academy of Child & Adolescent
Psychiatry. 39:975-94.
Barkley, R. A. (2000). Commentary on the multimodal treatment study of children with ADHD.
Journal of Abnormal Child Psychology, 28, 595-599.
Bauchner, H., & Sharfstein, J. (2001). Failure to report ethical approval in child health research:
Review of published papers. British Medical Journal, 323, 318-319.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Baughman F. (2000, September 29). The rise and fall of ADHD. Testimony before U.S.
Congress Committee on Education and the Workforce. Retrieved on February 5. 2003,
from http://www.house.gov/ed_workforce/hearings/106th/oi/ritalin92900/baughman.htm
Biederman, J., & Spencer, T. (2000). Non-stimulant treatments for ADHD. European Child &
Adolescent Psychiatry, 9(Suppl 1), I51-I59.
Biotechnology Industry Organization. 2003. FDA's Pediatric Rule:
History of Pediatric Studies,
Rule, Legislation and Litigation.
http://www.bio.org/reg/pedhist.asp
Birmaher, B., Waterman, G. S., Ryan, N. D., Perel, J., McNabb, J., Balach, L., et al. (1998).
Randomized, controlled trial of amitriptyline versus placebo for adolescents with
"treatment-resistant" major depression. Journal of the American Academy of Child &
Adolescent Psychiatry, 37, 527-535.
Black, K., Shea, C., Dursun, S., & Kutcher, S. (2000). Selective serotonin reuptake inhibitor
discontinuation syndrome: Proposed diagnostic criteria. Journal of Psychiatry and
Neuroscience, 25, 255-261.
Boseley, S. (1999, September 4). Revealed: The danger of taking Prozac. Drug maker knew 20
years ago of possible link to suicide. The Guardian, p. 1. Retrieved September 4, 1999
from http://www.guardian.co.uk/Print/0,3858,3898467,00.html.
Bowers, M. B., Jr., & Swigar, M. E. (1988). Psychotic patients who become worse on
neuroleptics. Journal of Clinical Psychopharmacology, 8, 417-421.
Breggin, P. R. (2000). A critical analysis of the Multimodal Treatment Study for attention-
deficit/hyperactivity disorder (the MTA study). Ethical Human Sciences and Services, 3,
63-72.
Breggin, P. R., & Breggin, G. R. (1994). The war against children. New York: St. Martins.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Breggin, P.R., & Cohen, D. (1999). Your drug may be your problem. Cambridge, MA: Perseus.
Brief of Amici Curiae. (2001, September 17). Grimes v. Kennedy Krieger, Court of Appeals of
Maryland. Filed by Association of American Medical Colleges, Association of American
Universities, Johns Hopkins University, and University of Maryland.
Carey, W. B. (2000). What the MTA study did and did not say about the use of methylphenidate
for attention deficits (Letter). American Journal of Pediatrics, 105, 863-864.
Carey, W. B. (2002). Is ADHD a valid disorder? In P. S. Jensen & J. R. Copper (Eds), Attention
deficit hyperactivity disorder: State of the science. Best Practices (pp. 3-19). Kingston,
NJ: Civic Research Institute.
Case Reports. (2002). Growth attenuation found in four pediatric patients on SSRIs. Brown
University Child and Adolescent Psychopharmacology Update, 4, 2-4.
http://www.medscape.com/viewarticle/442653
Castellanos, F. X. (2002) Proceed, with caution: SPECT cerebral blood flow studies of children
and adolescents with attention deficit hyperactivity disorder. Journal of Nuclear
Medicine. 43, 1630-1633.
Chakos, M. H., Lieberman, J. A., Bilder, R. M., Borenstein, M., Lerner, G., Bogerts, B.,
Wu, H., Kinon, B., & Ashtari, M. (1994). Increase in caudate nuclei volumes of
first-episode schizophrenic patients taking antipsychotic drugs. American Journal
of Psychiatry, 151, 1430-1436.
Coyle, J. (2000). Psychoactive drug use in very young children (Editorial). JAMA, 283.
Retrieved February 23, 2000 from http://jama.ama-
assn.org/issues/v283n8/ffull/jed90109.html

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Dembner, A. (2001a, February 18). Dangerous dosage. Boston Globe, p. 1. Retrieved February
18, 2001 from http://www.boston.com/dailyglobe2/049/nation/Dangerous_dosageP.shtml
Dembner, A. (2001b, March 20). Should a healthy child ever be a test subject? Boston Globe, p.
1. Retrieved March 20, 2001 from
http://199.97.97.16/contWriter/yhd7/2001/03/21/medic /4902-0204-pat_nytimes.html
Dembner, A. (2001c, March 25). Who's protecting the children? Drug research raises concerns
about policy and penalties. Boston Globe, p. 1. Retrieved March 25, 2001 from
http://www.boston.com/dailyglobe2/084/nation/Who_s_protecting_the_children_+.shtml
Department of Health & Human Services. (2001, last revised March 12). Draft policy and
procedures for DHHS research involving children — 45 CFR 46.407.
Diller L. (1998). Running on Ritalin: A physician reflects on children, society and performance
in a pill. New York. Bantam.
Diller, L. (2000, February 2). Over-medicating America's kids. Washington Post, p. A21.
Eli Lilly summary company profile. (2003) Business Week online. Retrieved June 15,
2003. http://research.businessweek.com/business_summary.asp?Symbol=LLY
Elliott, C. (2001, September 24-October 8) Pharma buys a conscience. The American Prospect,
(12 )17.
Drug Enforcement Agency. (1995). Methylphenidate: A background paper. Washington, DC:
United States Department of Justice.
Drug Enforcement Agency. (2000, May 16). Statement by Terrance Woodworth, Deputy
Director. Office of Diversion Control. Congressional testimony before the U.S.
[CONGRESS, SENATE?] Committee on Education and the Workforce: Subcommittee on

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Early Childhood, Youth and Families. Retrieved March 1, 2003 at:
http://www.usdoj.gov/dea/pubs/cngrtest/ct051600.htm
Faraone, S. V., Brown, C. H., Glatt, S. J., & Tsuang, M. T. (2002). Preventing schizophrenia and
psychotic behaviour: Definitions and methodological issues. Canadian Journal of
Psychiatry, 47, 527–537.
Food and Drug Administration. (1998, December 2, 1998). Regulations requiring manufacturers
to assess the safety and effectiveness of new drugs and biological products in pediatric
patients: Final rule. Federal Register, 63, 66631-66672.
Food and Drug Administration. (1999). Center for Drug Evaluation and Research. Pediatric
Subcommittee. November 5, 1999. Ethics Presentation Online. Ethical issues in pediatric
pharmaceutical research where there is no primary intention of direct benefit. Online at
http://www.fda.gov/cder/pediatric/pedethics-1199.htm
Food and Drug Administration (FDA). (2000a) Center for Drug Evaluation and Research.
Pediatric Information. FDA Ethics Working Group Consensus Statement on the Pediatric
Advisory Subcommittee's November 15, 1999 Meeting. April 19, 2000a. Final. Online at
http://www.fda.gov/cder/pediatric/ethics-statement.htm
Food and Drug Administration (FDA). (2000b). Center for Drug Evaluation and Research
website. Pediatric Depression: Background comments on pediatric depression. In Sample
Written Requests for Antidepressants. Online at:
http://www.fda.gov/cder/pediatric/antidepressant_ wr_template.htm
Food and Drug Administration. (2000c, March 23). Talk Paper: Janssen Pharmaceutica stops
marketing Cisapride in the US. Available on World Wide Web at:
http://www.fda.gov/bbs/topics/ANSWERS/ANS01007.htm

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Full disclosure. (2000, May 2). Editorial. Pittsburgh Post-Gazette. Retrieved May 2, 2000 from
http://www.post-gazette.com/forum/20000502eddrugtest1.asp
Garnett, L. R. (2000, May 7). Prozac revisited: As drug gets remade, concerns about suicides
surface. Boston Globe, p. 1.
Glantz, L. (1998). Research with children. American Journal of Law & Medicine, 24, 214-244.
Glenmullen, J. (2000). Prozac backlash. New York: Simon & Schuster.
Goode, E. (1999, December 7). Doctors try a bold move against schizophrenia. New York Times,
p. F1.
Goode, E. (2000, July 18). Once again, Prozac takes center stage, in furor. New York Times.
Retrieved July 18, 2000 from
http://www.nytimes.com/library/national/science/health/071800hth-behavior-prozac.html
Gorman, J. M., Kent, J., Martinez, J., Browne, S., Coplan, J., & Papp, L. A. (2002).
Physiological changes during carbon dioxide inhalation in patients with panic disorder,
major depression, and premenstrual dysphoric disorder: Evidence for a central fear
mechanism. Archives of General Psychiatry, 59, 567-569.
Greeley, W. (2002). Pediatric clinical trials: Shall we take a lead? (Editorial). Anesthesia and
Analgesia, 94, 1-3.
Grimes v Kennedy-Krieger Institute. Maryland Court of Appeals. August 16, 2001. Available
online at http://www.courts.state.md.us/opinions/coa/2001/128a00.pdf
Grinfeld, M. (1998, March). Psychoactive medications and kids: New initiatives launched.
Psychiatric Times, 14 (3): 69.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Gur, R. E., Cowell, P., Turetsky, B. I., Gallacher, F., Cannon, T., Bilker, W., & Gur, R. C. (1998). A
follow-up magnetic resonance imaging study of schizophrenia. Archives of General
Psychiatry, 55, 145-152.
Gur, R.E., Maany, V., Mozley, P. D., Swanson, C., Bilker, W., & Gur, R. C. (1998). Subcortical
MRI volumes in neuroleptic-naive and treated patients with schizophrenia. American
Journal of Psychiatry, 155, 1711-1717.
Harrison P. J. (1999). The neuropathological effects of antipsychotic drugs. Schizophrenia
Research, 40, 87-99.
Healy, D. (1997). The antidepressant era. Cambridge, MA: Harvard University Press.
Healy, D. (2000). Emergence of antidepressant induced suicidality. Primary Care Psychiatry, 6,
25-28.
Healy, D. (2002a). Randomized controlled trials: Evidence biased psychiatry. Available online
at:
http://www.ahrp.org/COI/healy0802.html
Healy, D. (2002b) Testing psychotropic drugs in
children. Available online at:
http://www.ahrp.org/children/healy0402.html
Hegarty, J. D., Baldessarini, R. J., Tohen, M., Waternaux, C., & Oepen, G. (1994). One hundred
years of schizophrenia: A meta-analysis of the outcome literature. American Journal of
Psychiatry, 151, 1409-1416.
Huget, J. (2001, January 2). Scandal! They haven't tested Ritalin on the children it's prescribed
for! Scandal! They're going to test Ritalin on the children! Washington Post, p. T-6.
Hyman, S. E., & Nestler, E. J. (1996). Initiation and adaptation: A paradigm for understanding
psychoactive drug action. American Journal of Psychiatry, 153, 151-162.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Hypericum Depression Trial Study Group. (2002). Effect of Hypericum perforatum (St John's
Wort) in major depressive disorder: A randomized controlled trial. Journal of the
American Medical Association, 287, 1807-1814.
Institute of Medicine. (2002, October 3) Report. Responsible research: a systems
approach to protecting research participants. Washington, DC: The National Academies
Press. Retrieved on April 15, 2003 at: http://www.nap.edu/books/0309084881/html/
Jablensky, A. (2000). Prevalence and incidence of schizophrenia spectrum disorders:
Implications for prevention. Australian and New Zealand Journal of Psychiatry,
34(Suppl), S26-S34.
Jauss, M. (1998). Severe akathisia during olanzapine treatment of acute schizophrenia.
Pharmacopsychiatry, 31, 146-148.
Jetter, A. (2000, September 12). Efforts to test drugs on children hasten drive for research
guidelines. New York Times. Retrieved September 12, 2000 from
http://www.nytimes.com/yr/mo/day/ science/12ETHI.html
Khan, A., Warner, H. A., & Brown, W. A. (2000). Symptom reduction and suicide risk in
patients treated with placebo in antidepressant clinical trials: An analysis of the Food and
Drug Administration database. Archives of General Psychiatry 57, 311-317.
Khan A., Khan, S. R., Leventhal, R. M., Krishnan, K. R., & Gorman, J. M. (2002).
An application of the revised CONSORT standards to FDA summary reports of recently
approved antidepressants and antipsychotics. Biological Psychiatry, 52, 62-67.
Kaiser, D. (1996, December). Against biologic psychiatry. Psychiatric Times, 13. Retrieved
January 30, 2003 from http://www.mhsource.com/pt/p961242.html.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Kalia, M., O’Callaghan, J. P., Miller, D. B., Kramer, M. (2000). Comparative study of
fluoxetine, sibutramine, sertraline and dexfenfluramine on the morphology of
serotonergic nerve terminals using serotonin immunohistochemistry. Brain Research.
858(1), 92-105.
Kendler, K., & Diehl, D. (1993). The genetics of schizophrenia: A current, genetic-
epidemiologic perspective. Schizophrenia Bulletin, 19, 261-285.
King, R. A., Riddle, M. A., Chappell, P. B., Hardin, M. T., Anderson, G. M., Lombroso, P.,
Scahill, L. (1991). Emergence of self-destructive phenomena in children and adolescents
during fluoxetine treatment. Journal of the American Academy of Child and Adolescent
Psychiatry, 30, 179-186.
Kirsch, I., Moore, T. J., Scoboria, A., & Nicholls, S. S. (2002). The Emperor's new drugs: An
analysis of antidepressant medication data submitted to the U.S. Food and Drug
Administration. Prevention & Treatment, 5, Article 23. Available at:
http://journals.apa.org/prevention/volume5/pre0050023a.html
Klassen, T. P., Wiebe, N., Russell, K., Stevens, K., Hartling, L., Craig, W. R., & Moher, D.
(2002). Abstracts of randomized controlled trials presented at the society for pediatric
research meeting: An example of publication bias. Archives of Pediatric and Adolescent
Medicine, 156, 474-479.
Klein , R. G., Mannuzza, S., Koplewicz, H. S., Tancer, N. K., Shah, M., Liang, V., & Davies M.
(1998). Adolescent depression: Controlled desipramine treatment and atypical features.
Depression & Anxiety, 7, 15-31.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Koller, E., Malozowski, S., & Doraiswamy, P. M. (2001). Atypical antipsychotic drugs and
hyperglycemia in adolescents (Letter). JAMA, 286. Retrieved November 28, 2001from
http://jama.ama-assn.org/issues/current/ffull/jlt1128-4.html.
Konradi, C., Leveque, J. C., Hyman, S. E. (1996). Amphetamine and dopamine-induced
immediate early gene expression in striatal neurons depends on postsynaptic NMDA
receptors and calcium. Journal of Neuroscience, 16, 4231-4239.
Kutcher, S. (1997). Practitioner review: The pharmacotherapy of adolescent depression. Journal
of Child Psychiatry, 38, 755-767.
Kye, C. H., Waterman, G. S., Ryan, N. D., Birmaher, B., Williamson , D. E., Iyengar, S., &
Dachille, S. (1996). A randomized, controlled trial of amitriptyline in the acute treatment
of adolescent major depression. Journal of the American Academy of Child Adolescent
Psychiatry. 35, 1139-1144.
Lambert , N. M., & Hartsough, C. S. (1998). Prospective study of tobacco smoking and
substance dependencies among samples of ADHD and non-ADHD participants. Journal
of Learning Disabilities, 31, 533-544.
Lambert, N. M. (1998). Stimulant treatment as a risk factor for nicotine use and substance abuse.
Presented at NIMH Consensus Conference, available online from
http://www.add.about.com/health/add/library/weekly/aa1119v.htm
Leo, J. (2002, January/February). American preschoolers on Ritalin. Society, 39, 52-60.
Lieberman, J. A., Sheitman, B. B., Kinon, B. J. (1997). Neurochemical sensitization in the
pathophysiology of schizophrenia: Deficits and dysfunction in neuronal regulation and
plasticity. Neuropsychopharmacology, 17, 205-229.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Madsen, A. L., Keidling, N., Karle, A., Esbjerg S, Hemmingsen R. (1998). Neuroleptics in
progressive structural brain abnormalities in psychiatric illness. Lancet, 352, 784-785.
March, J. S., Biederman, J., Wolkow, R., Safferman, A., Mardekian, J., Cook, E. H., et al.
(1998). Sertraline in children and adolescents with obsessive-compulsive disorder. JAMA,
280, 1752-1756.
Marshall, E. (2000a). Planned Ritalin trial for tots heads into uncharted waters. Science, 290,
1280-1281.
Marshall, E. (2000b). Duke study faults overuse of stimulants for children. Science, 389, 721.
Martin, S. (2000, October 5). Are schools pushing Ritalin? Congress gets involved in the
controversy. WebMD. Retrieved December 10, 2002
http://webmd.lycos.com/content/article/1728.61890
Mazo, E. (2000, April 27). Infant's death raises alarms on who's used in drug trials. Pittsburgh
Post-Gazette. Retrieved April 27, 2000 from
http://www.postgazette.com/healthscience/20000427propulsid1.asp
McKeen, D. (2000). The ethics of drug testing: Kids as guinea pigs. Salon. Retrieved May 31,
2000 from http://www.salon.com/health/feature/2000/05/31/drug_trials/index2.html
Mezzacappa, E., Steingard, R., Kindlon, D., Saul, J. P., & Earls, F. (1998). Tricyclic
antidepressants and cardiac autonomic control in children and adolescents. Journal of the
American Academy of Child & Adolescent Psychiatry, 37, 52-59.
Mittleman, B. B., Castellanos, F. X., Jacobsen, L. K., Rapoport, J. L., Swedo, S. E., & Shearer ,
G. M. (1997). Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease.
Journal of Immunology, 159, 2994-2999.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Montero, D. (2001, February 12). Risking kids' health for sake of science. New York Post.
Retrieved February 12, 2001 from
http://members.fortunecity.com/siriusw/riskingkids.htm
Moore, T.J. (1997, December). Hard to Swallow. The Washingtonian. Available online at:
http://www.washingtonian.com/health/hardtoswallow.html
Moore, T. J. (1998). Prescription for disaster. Simon & Schuster, 1998.
MTA Cooperative Group. (1999a). A 14-month randomized clinical trial of treatment strategies
for attention-deficit/hyperactivity disorder. Archives of General Psychiatry, 56, 1073-
1086.
MTA Cooperative Group. (1999b). Moderators and mediators of treatment response for children
with attention-deficit/ hyperactivity disorder: The Multimodal Treatment Study of
children with attention-deficit/hyperactivity disorder. Archives of General Psychiatry, 56,
1088-1096.
Murphy, D. (2001). Challenges unique to pediatric new product development (Slide
presentation). Retrieved May 31, 2002 from http://www.wcuppd.org/pediatric/sld013.htm
National Institutes of Health. (1998, March 6). NIH policy and guidelines on the inclusion of
children as participants in research involving human subjects. Available online:
http://grants.nih.gov/grants/guide/notice-files/not98-024.html
Neergaard, L. (2000, February 15). A warning for tiny hearts: Safety of heartburn drug Propulsid
in question. Pittsburgh Post-Gazette. Retrieved on February 28, 2003 from
http://www.msbp.com/propulsid.htm

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Neergaard, L. (2000a, December 12). FDA cast doubts on doctors: New drug warnings often
ignored. Associated Press release retrieved December 12, 2000 from
http://abcnews.go.com/sections/living/DailyNews/drugban001212.html
Neergaard, L. (2000b, February 7). Is Propulsid safe for babies? Associated Press release
retrieved February 7, 2000 from
http://onhealth.webmd.com/baby/briefs/reuters/item%2C79331.asp
The Need to Test Drugs on Children . (2002, April 7). Editorial. New York Times. Retrieved
April 7, 2002 from
http://www.nytimes.com/2002/04/07/opinion/07SUN2.html?pagewanted=print&position
=top
Pfizer. (1996, May 23). Suicide-related behavior in children and adolescents in the sertraline
OCD clinical development program. Safety Evaluation and Epidemiology. Report
submitted to the FDA. Obtained under Freedom of Information Act.
Pfizer. (1997). Expert Report on the clinical documentation of sertraline hydrochloride for
obsessive compulsive disorder in paediatric patients. Report submitted to the FDA.
“Approved October 20, 1997.” Obtained under Freedom of Information Act.
Picard A. (2002, May 29). Pediatrics data buried if negative, study says. Globe and Mail
(Toronto), p. A8. Also available online from:
http://www.antidepressantsfacts.com/Pediatrics-data-buried.htm
Pine DS, Coplan JD, Wasserman GA, Miller LS, Fried JE, Davies M, Cooper TB, Greenhill L
Shaffer D, Parsons B. (1997). Neuroendocrine response to fenfluramine challenge in
boys. Archives of General Psychiatry. 54: 839-846.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Lurie, P., & Wolfe, S. (1998, December). FDA medical officers report lower standards permit
dangerous drug approvals. Public Citizen report, available online:
http://www.citizen.org/publications/release.cfm?ID=7104
Public Citizen. (2000) Report by Australian Adverse Drug Reactions Advisory Committee.
(1999) Available online: http://www.citizen.org/eletter/ARTICLES/olanzapine.htm
Public Citizen. (2001a, July 23) Report. The other drug war: big pharma's 625 Washington
lobbyists. http://www.citizen.org/congress/drugs/pharmadrugwar.html
Public Citizen. (2001b, November 9). Patently offensive: Congress set to extend monopoly
patents for Cipro and other Drugs. Retrieved November 2002
http://www.citizen.org/congress/reform/drug_patents/pediatric/articles.cfm?ID=6435
Riddle, M. A., Hardin, M. T., King, R., Scahill, L., & Woolston, J. L. (1990). Fluoxetine
treatment of children and adolescents with Tourette's and obsessive compulsive
disorders: Preliminary clinical experience. Journal of the American Academy of Child
and Adolescent Psychiatry, 29, 45-48.
Riddle MA, Geller B, Ryan N. (1993) Another sudden death in a child treated with desipramine.
Journal of the Americn Academy of Child and Adolescent Psychiatry, 32:792-7
Roberts, R. (2002, October 15) Presentation.The Federal Government: Recent Changes at FDA and the
Implications for Pediatric Clinical Trials. Retrieved on February 15, 2003:
http://www.fda.gov/cder/pediatric/presentation/wustl-Roberts2002/sld001.htm
Rushton, J. (2000). Ritalin and Prozac: More kids using both drugs. Abstract from Pediatric
Academic Societies, retrieved June 1, 2001 from
http://www.wcanews.com/archives/2000/Jul/jul0300d.htm
Rustad, M. (2000, March 7) Antidepressants found to alter brain cells in rats. Retrieved

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
December 15, 2002 from
http://www.psycport.com/news/2000/03/06/tbl-z/8363-0008-
ANTIDEPRESSANTS-BRAIN.html
and http://www.rense.com/ufo6/braincell.htm
Sabo, E. (2001, January 23). Fuzzy math in drug studies. Medscape Health. Retrived January 23,
2001 from http://health.medscape.com/cx/viewarticle/232469
Sharav, V. H. (2001, April 5). Comments concerning “Draft policy and procedures for DHHS
research involving children — 45 CFR 46.407. Unpublished manuscript submitted to
Office of Human Research Protections.
Sharav, V. H. (2002, May 6). Conflicts of interest. Paper presented at U.S. Army Medical
Department and Henry Jackson Foundation, San Antonio, Texas. Available online from
http://www.ahrp.org/testimonypresentations/armymeddept.html
Sherman, C. (2002) Antisuicidal effect of psychotropics remains uncertain. Clinical Psychiatry
News. August 2002, 30: p1
Siberry, G. K., Iannone, R., & Childs, B. (Eds.). (2000). Harriet Lane handbook: A manual for
pediatric house officers (15
th
ed.). Baltimore, MD: Mosby Publishers.
Spice, B. (2000, July 9). Was baby treated for ailment he didn't have? Pittsburgh Post-Gazette.
Retrieved July 9, 2000 from http://www.post-gazette.com/healthscience/20010709gage
0709p5.asp
Steinbrook R. (2002) Testing medications in children. New England Journal of Medicine, 347,
1462-1470.
Stolberg, S. G. (2001, February 11). As children help test medicines, profits and questions are
raised. New York Times. Retrieved February 11, 2001 from
http://www.nytimes.com/2001/02/11/national/11DRUG.html

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Surgeon General. (1999). Mental health: A report of the Surgeon General (Chapter 3: Children).
Available on World Wide Web at:
http://www.surgeongeneral.gov/library/mentalhealth/toc. html#chapter3
Surgeon General. (2001, January 3). Report of the Surgeon General's conference on children's
mental health: National action agenda. Available on World Wide Web at:
http://www.surgeongeneral.gov/cmh/childreport.htm
Swanson, J. M., Kraemer, H. C., Hinshaw, S. P., Arnold, L. E., Conners, C. K., Abikoff, H. B., et
al. (2001). Clinical relevance of the primary findings of the MTA: Success rates based on
severity of ADHD and ODD symptoms at the end of treatment. Journal of the American
Academy of Child & Adolescent Psychiatry, 40, 168-179.
Swanson, J. R., Jones GR, Krasselt W, Denmark LN, Ratti F. (1997). Death of two subjects due to
imipramine and desipramine metabolite accumulation during chronic therapy: A review
of the literature and possible mechanisms. Journal of Forensic Science, 42, 335-339.
Tanouye, E. (1999, August 25). New weapons in the war on schizophrenia. Wall Street Journal,
p. B-1.
Teicher, M. H., Glod, C., & Cole, J. O. (1990). Emergence of intense suicidal preoccupation
during fluoxetine treatment. American Journal of Psychiatry, 147, 207-210.
Teicher MH, Glod CA, Cole JO. (1993). Antidepressant drugs and the emergence of suicidal
tendencies. Drug Safety.8:186-212, p. 186.
Teva Pharmaceuticals USA. (2000) Comments on the content of FDA’s report to Congress on
pediatric exclusivity issues. Docket no. OON-1266, June 2. Retrieved January 18, 2003
from http://www.fda.gov/ohrms/dockets/dailys/00/jun00/060500/c00003.pdf
The Prozac question (Editorial). (2000, June 13). Boston Globe, p. A-26.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Tsuang, M. T., & Faraone, S. V. (2002a). Diagnostic concepts and the prevention of
schizophrenia. Canadian Journal of Psychiatry, 47, 515-517.
Tsuang, M. T., Stone, W. S., & Faraone, S.V. (2000).
Toward reformulating the diagnosis of
schizophrenia.
American Journal of Psychiatry, 157, 1041-1050.
Tsuang, M. T., Stone, W. S., & Faraone, S. V. (2002b). Understanding predisposition to
schizophrenia: Toward intervention and prevention. Canadian Journal of Psychiatry, 47,
518–526.
Tsuang, M.T. & Faraone, S.V. (2002c). (Editorial) Diagnostic Concepts and the Prevention of
Schizophrenia. Canadian Journal of Psychiatry, 47, 515-7.
United States Code of Federal Regulations. (1983) US 45 CFR 46, Subpart D “Additional Protections for
Children” were adopted March 8, 1983. Retrieved November 2001 from
http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm#46.405
.
U.S. Public Law. 102-571 (1992). 21 USC 301.
U.S. Public Law 105-115. (1997) 21 USC 301)
Valenstein, E. (1998). Blaming the brain: The truth about drugs and mental health. New York:
The Free Press.
Van Putten, T., & Marder, S. R. (1987). Behavioral toxicity of antipsychotic drugs. Journal of
Clinical Psychiatry, 48(Suppl.), 13-19.
Van Reekum, R., & Cleghorn, J. M. (1992). Pamphlet #9: Report on the evidence supporting a
biological basis for schizophrenia. Toronto: World Fellowship for Schizophrenia and
Allied Disorders. Retrieved Month, Day, Year from http://www.world-
schizophrenia.org/publications/09-biological/html

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Varley, C. K., & McClellan, J. (1997). Case study: two additional sudden deaths with tricyclic
antidepressants. Journal of the American Academy of Child & Adolescent Psychiatry, 36,
390-394.
Vastag, B. (2001). Pay attention: Ritalin acts much like cocaine. JAMA, 286. Retrieved August
29, 2001 from http://jama.ama-assn.org/issues/v286n8/ffull/jmn0822-1.html
Vitiello, B., Jensen, P. S., & Hoagwood, K. (1999). Integrating science and ethics in child and
adolescent psychiatry research. Biological Psychiatry, 46, 1044-1049.
Vitiello, B. (2001). Psychopharmacology for young children: Clinical needs and research
opportunities. Pediatrics, 108, 983-990. .
Voelker, R. (1999). SSRI use common in children. JAMA, 281. Retrieved May 26, 1999 from
http://jama.ama-assn.org/issues/v281n20/ffull/jqu90003-3.html
Volkow, N. D., Ding, Y. S., Fowler, J. S., Wang, G. J., Logan, J., Gatley J. S., et al. (1995). Is
methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the
human brain. Archives of General Psychiatry, 52, 456-463.
Whitaker, R., & Kong, D. (1998, November 15-18). Doing harm: Research on the mentally ill
(Investigative series). Boston Globe, p. 1.
Whitaker, R. (2002). Mad in America. Cambridge, MA: Perseus.
Wilens, T. E., Biederman, J., Baldessarini, R. J., Geller, B., Schleifer, D., Spencer, T.J.,
Birmaher , B., & Goldblatt, A. (1996). Cardiovascular effects of therapeutic doses of
tricyclic antidepressants in children and adolescents. Journal of the American Academy of
Child & Adolescent Psychiatry, 35, 1491-1501.
Willman, D. (1998, December 6). “Fast-track” drug to treat diabetes tied to 33 deaths. Los
Angeles Times, p. 1.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Willman, D. (2000a, December 20). How a new policy led to seven deadly drugs. Los Angeles
Times, p. 1. Retrieved December 20, 2000 from
http://www.latimes.com/news/nation/reports/fda/lat_fda001220.htm
Willman, D. (2000b, December 20). Propulsid: A heartburn drug, now linked to children's
deaths. Los Angeles Times, p. 1. Retrieved December 20, 2000 from
http://www.pulitzer.org/year/2001/investigative-reporting/works/willman2.html
Wirshing W, VanPutten T, Rosenberg, J, Marder S, Ames D, Hicks-Gray T. (1992). Fluoxetine, akathisia, and
suicidality: is there a causal connection? Archives of General Psychiatry, 49: 580-581.
World Health Organization. (2000, November 3). WHO Pharmaceuticals Newsletter. Uppsala,
Sweden: WHO Collaborating Centre for International Drug Monitoring. Available on
World Wide Web at: http://www.who.int/medicines/library/pnewslet/pn32000.html
Zimmerman M, Mattia JI, Posternak MA. 2002. Are subjects in pharmacological treatment trials of
depression representative of patients in routine clinical practice? AJP. 159::469-73.
Zimmerman, R. (2000, July 26). Radical study on schizophrenia may be expanded: Researchers
seek to discover whether antipsychotic drugs can prevent the disease. Wall Street
Journal. Retrieved July 26, 2000 from
http://www.contac.org/contaclibrary/research70.htm
Zimmerman, R. (2001, February 5) Drug makers find a windfall testing adult drugs on kids. Wall
Street Journal, p. 1.
Zito, J.M., Safer D. J., dosReis, S., Gardner, J. F., Boles, J., & Lynch, F. (2000). Trends in the
prescribing of psychotropic medications to preschoolers. JAMA, 283, 1025-1030.

Impact of FDAMA Children
Ethical Human Sciences and Services
Summer 2003, vol 5 no2, pp 83-108
Zito, J. M., Safer, D. J., dosReis, S., Gardner, J. F., Magder, L., Soeken, K., et al. (2003).
Psychotropic practice patterns for youth: A 10-year perspective. Archives of Pediatric
and Adolescent Medicine, 157, 17-25.
Zuckoff, M. (2000, June 11). Prozac new directions: Science, money drive a makeover. Boston
Globe, p. 1.