FDA Mulls Child Stimulant Ethics

Irving News Comments
September 3, 2004
Reproduced with Permission

[Note: How soon we forget! My thesis as a biochemistry major involved the infamous "twin" experiments of Nazi "scientist" Mengele, where one twin was used as the "control", and the other twin was experimented on. Thus it is startling to me to see that only 60 years later, the research community seems to have forgotten those massive and horrific abuses of human subjects, and is now "confused" as to the "ethics" involved in research involving children as "controls" (see article below). The extraordinarily harsh ethical lessons learned back then that resulted in the Nuremberg Code are now merely snickered at by many researchers, but perhaps that Code should be revisited -- especially given the immense number of human subjects that will be statistically required to participate internationally in the nano/bio/info/cogno "Future" looming before us.

The Nuremberg Code requires that only human subjects that can give legally valid informed consent may participate in biomedical research. Children by definition, cannot give truly legal informed consent to participate in biomedical research -- whether "therapeutic" or "experimental". Another international research Code, The Declaration of Helsinki, also stipulates that therapeutic research must directly benefit the patient, and that patients should not be used simply for "the advancement of science" or for the "greater good of society":

"Concern for the interests of the subject must always prevail over the interests of science and society [Basic principles]... The physician can combine medical research with professional care, the objective being the acquisition of new medical knowledge, only to the extent that medical research is justified by its potential diagnostic or therapeutic value for the patient [Medical research combined with clinical care - clinical research]... In research on man, the interests of science and society should never take precedence over considerations related to the wellbeing of the subject (non-therapeutic biomedical research involving human subjects - non-clinical biomedical research]."

[Declaration of Helsinki at A6-4 to A6-6]

Thus one of the lessons of Nuremberg and Helsinki was that, although perhaps heroic, human subjects are not ethically required to offer themselves as guinea pigs in research -- especially when the means used includes the design of the protocol itself as simply and only to study the process of a disease (as in the research described below), rather than to hopefully benefit the patient. This is precisely why the infamous Tuskegee experiments using black men to "study the process of syphilis", and the use of mentally retarded children in orphanages to "study the effect of radiation" slipped into their cereal, were inherently unethical and ultimately condemned by the medical research community. [See also, e.g., an example of such research in which patients with schizophrenia were enrolled in clinical trials for the sole purpose of studying the process of relapse during "washouts": Shamoo and Irving, "Accountability in research with persons with mental illness", Accountability in Research Nov. 1993, 3(1):1-17, at: http://www.lifeissues.net/writers/irv/irv_12mentalillness1.html -- DNI]

Nor are parents ethically required to offer their children as guinea pigs, even if the utilitarian "risks" vs. the "benefits" are "low". When such utilitarian participation begins to be "ethically" or "legally" required, we will find ourselves right back at Nuremberg.

Of additional concern is that our own U.S. federal regulations involving human subjects in research are grounded on The Belmont Report (1978), the same one which gave "birth" to "bioethics". In that Report, all citizens have a "strong moral duty" to participate in purely experimental research "for the greater good of society"! Also in that Report, "beneficence" is strongly defined as the "good" to society, and "justice" is defined after Rawls -- i.e., the fair distribution of the risks and benefits of research"! Hopefully the FDA's decision on the "twins experiments" discussed below will be grounded on more ethical "research ethics" than this. -- DNI]


Sep 3, 2:02 PM EDT

FDA Mulls Child Stimulant Ethics

AP Science Writer

WASHINGTON (AP) -- Is it ethical in the name of science to give a healthy child as young as 9 a controlled substance? That's the dilemma facing the Food and Drug Administration's Pediatric Ethics subcommittee at its first-ever meeting on Sept. 10.

The research, proposed by the National Institute of Mental Health, includes healthy children among 9- to 18-year-olds who would receive a single 10 mg. dose of dextroamphetamine.

The hoped-for payoff for research: A better understanding of how healthy brains work differently from those of children diagnosed with attention deficit hyperactivity disorder.

The payoff for families: $570.

Characterized by inattentiveness, overactivity and impulsiveness, ADHD affects up to 5 percent of schoolchildren. The disorder continues in roughly 60 percent of those youths as they age, although experts say the disorder is underdiagnosed in adults.

Dextroamphetamine, the active ingredient in such drugs as Dexedrine and Adderall, is prescribed commonly to increase attention span and calm restlessness. Doses vary with children's needs, with daily doses as little as 5 mg. or as much as 30 mg.

Judith L. Rapoport, chief of child psychology at NIMH, within the National Institutes of Health, conducted a similar trial 20 years ago. The same stimulant was given to children at a higher dose. Researchers looked only at how the stimulant changed children's behavior as they performed tasks. The stimulant improved attention span in the children, regardless of whether they had ADHD.

The new trial would add magnetic resonance images to map potential differences in brain activation patterns.

While Rapoport's trial is little different from the earlier one, review boards that balance risk vs. scientific gain have changed dramatically in 20 years.

Indeed, an NIH review panel met twice and was unable to reach a consensus whether risk to healthy volunteers would be too high in the new study. They kicked the sensitive matter over the FDA's new pediatrics ethics subcommittee.

The study would involve 14 children with ADHD, 14 healthy children, 12 pairs of identical twins and 12 pairs of fraternal twins. As the children completed specified tasks, their brain activity would be captured by MRIs.

Comparing twins - one with ADHD, the other normal - helps researchers tease out genetic explanations of differences in response to treatment.

In September 2003, an NIMH panel that reviewed the proposal's scientific merit called the program an excellent submission. The panel noted that it would be the first ADHD study to compare twins, which has been useful in past studies on schizophrenia.

The panel that considers a safety of human subjects, however, was troubled by the youngest tested children's age and the potential for coercion because each participant would be paid $570 for the 11-hour study.

The major stumbling block was determined to be the risk of giving a class 2 controlled substance to healthy children, which some fretted might breed future substance abuse.

Children in the 1980 NIH trial had no increased risk of drug abuse in the five years after the trial ended, researchers say in the study protocol.

The most common side effects among healthy children given a single dose of the stimulant in past experiments was temporary insomnia and poor appetite. One brain-damaged child exposed to the medication suffered hallucinations.

Many ethicists expect the FDA subcommittee to use a primary litmus test: Does taking the stimulant pose more than a minimal increase to risks that healthy children face in everyday life?

Pearl O'Rourke, who oversees human research affairs, interviewed the heads of six review boards at Massachusetts General and Brigham and Women's Hospital.

"Five said they would not approve this study. And all five said, 'But we wish we could,'" O'Rourke said during a March 3 NIH discussion.

O'Rourke acknowledged that the review boards struggle with murky federal regulations, tightening case law, financing agencies that prefer pediatric studies and the threat of negative media coverage.

"I live in dread fear of what's going to be on the front page of the paper," she told the audience. "So, when I heard this, three things hit my mind: Kids, ohmigod! Psychiatric disease. And a class 2 drug."

The FDA panel could simply approve the plan if it should find it carried great scientific weight, said Dr. Douglas Diekema, director of medical ethics at Children's Hospital in Seattle.

New Jersey attorney Alan C. Milstein said that would be the wrong call.

Milstein, who represented the family of an 18-year-old whose death in 1999 spurred greater federal oversight of gene therapy trials, pointed to a recent Maryland Supreme Court ruling. The court held that exposing healthy children to higher-than-minimum risk in a medical study is unethical.

"They can't do this study. It doesn't take a genius to figure out why they can't do it," Milstein said. "I can't believe that anybody is going to say it's ethical to do this. It's not even a close call."

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© 2004 The Associated Press.