The Office for Protection from Research Risks (OPRR), an agency operating under the aegis of the U.S. Department of Health and Human Services, launched an investigation in April aimed at determining whether young boys were endangered during the course of experiments involving the drug fenfluramine (Pondimin).
The Office for Protection from Research Risks (OPRR), an agency operating under the aegis of the U.S. Department of Health and Human Services, launched an investigation in April aimed at determining whether young boys were endangered during the course of experiments involving the drug fenfluramine (Pondimin). Complaints lodged by Disability Advocates, Inc., the Disability Law Center of the New York Lawyers for the Public Interest, Inc., and the Citizens for Responsible Care in Psychiatry & Research-all New York-based consumer advocacy groups-charged that investigators exposed children to "risky, nontherapeutic experiments" that were unethical and illegal.
Ironically, the charges come at the same time the U.S. Food and Drug Administration has launched an initiative to increase pediatric drug research. As a result, while researchers are buoyed by the prospect of greater resources for investigating serious childhood illnesses, they are also concerned by what they see as baseless complaints and unjustified attacks in the media that can produce a chilling effect on pursuing important scientific inquiries.
According to the watchdog groups, the Columbia University-affiliated New York State Psychiatric Institute (NYSPI), the department of psychology at Queens College of the City of New York, and the department of psychiatry at the Mount Sinai School of Medicine violated federal research regulations in experiments supported, at least in part, by the National Institute of Mental Health and other National Institutes of Health funding. In each of the studies, young boys underwent a "challenge" with the diet drug fenfluramine as a means of investigating hypothetical associations between serotonergic activity and aggression.
In letters to the OPRR, the research facilities were charged with performing experiments that provided no potential benefit to the child subjects and offered no prospect of understanding a medical condition. Under these circumstances, the critics claimed, the risks assumed by the participants violated federal laws and regulations on human subjects research.
All of the research institutions have emphatically denied the critics' allegations, insisting that they anticipate the OPRR investigation will clear them of any wrongdoing. Results of their studies appeared in three published articles, including "Neuroendocrine Response to Fenfluramine Challenge in Boys" (Arch Gen Psychiatry  54:839-846), "Age-Related Changes in the Association between Serotonergic Function and Aggression in Boys with ADHD" (Biol Psychiatry  41:682-689) and "Serotonin Aggression and Parental Psychopathology in Children with Attention-Deficit Hyperactivity Disorder" (J Am Acad Child Adolesc Psychiatry  36:1391-1398).
Thus far, no one has claimed that any child was actually harmed by participation in the studies, although public anxiety increased after the FDA forced manufacturers to withdraw fenfluramine from the market last year. The government action was taken after the Mayo Clinic in Rochester, Minn., reported a statistical correlation between heart valve damage and the extended use of fenfluramine and dexfenfluramine (Redux). Single doses of fenfluramine, like those used in the criticized research, however, have never been clinically correlated to serious side effects.
It will take months before the OPRR concludes its investigation, according to its director, Gary B. Ellis, M.D. In a telephone interview with Psychiatric Times he confirmed that the agency is "evaluating the protection of human subjects" based on "allegations" related to the institutions' use of fenfluramine in research.
"The regulations of the Department of Health and Human Services...describe specific pathways by which research involving children may be approved and conducted ethically," Ellis said. "It follows that certain proposed research lies outside of those pathways." The agency's job, he added, is to determine whether or not any particular research study is on the "pathway." Ellis declined to comment on whether his agency's goals are at odds with efforts underway at the FDA.
Meanwhile, the charges leveled against the research institutions have produced a storm of controversy, including claims that the studies were racially and ethnically motivated. The NYSPI study in particular was singled out because all its 34 participants were African American or Hispanic. In press accounts, critics of the studies correlated the research to the Tuskegee experiments in which African American men with syphilis went untreated for experimental reasons. The Rev. Al Sharpton, the controversial civil rights advocate who unsuccessfully ran for New York City mayor last year, even called for a criminal investigation into whether the NYSPI study improperly accessed juvenile court records.
Jack Gorman, M.D., a psychopharmacologist and NYSPI's deputy director, bristled at the complaints and told Psychiatric Times that he viewed them as "provocative" and "ridiculous."
"The New York State Psychiatric Institute stands behind its research as being scientifically important and ethical and we are certain that proper scrutiny of our work will be consistent with that position," he said. "Assaults like this on properly conducted research will certainly have the effect of putting barriers to further scientific work in this area. This will only mean that people suffering from significant psychiatric problems will be denied access to all the benefits of current biomedical technology and, therefore, will continue to be second class citizens when compared to people suffering from other illnesses."
The NYSPI study, geared toward determining whether environmental circumstances can effect brain changes that increase the likelihood of youthful aggression, has now been put on hold. The research, Gorman said, would have allowed scientists to determine whether there were ways to gauge the propensity for violent youthful behavior at an early age, and to determine what interventions could undo any physiological damage caused by impoverished and socially unhealthy environments. The fenfluramine challenge, only part of a broad range of neuro-psychological and medical testing, was designed to measure central serotonergic activity on the male siblings of convicted delinquent boys.
Even a go-ahead from the OPRR in the future won't necessarily mean that NYSPI will restart the research. "You can already see the negative results on this kind of research. Scientists, because they feel attacked and insulted, and because they are unable to do their work as a result of the time commitment necessary to answer all of these things, decide not to pursue these projects," Gorman said. "We would have to be assured in our own minds that we won't get into another situation where we will continue to have to answer all of these critics."
Gorman is particularly incensed by the charges of racism, saying that the subjects ended up being African American and Hispanic because of the composition of the neighborhood in which they were selected. The comparison to Tuskegee, he said, "demeans its seriousness" and "trivializes the terrible things that were done there." "There is not the vaguest similarity between any research ever conducted at this institution and anything that happened there."
In an interview with Psychiatric Times, David B. Pruitt, M.D., director of the division of child psychiatry at the University of Tennessee, Memphis Health Science Center, and president of the American Academy of Child and Adolescent Psychiatry, said that part of the controversy relates to the stigma issue, and asked, "Is a child psychiatrist and is child psychiatry in general held to different standards than the rest of medicine and the rest of the scientific community?"
He added that the institutional review boards at the local and national levels should be relied on to provide the safeguards necessary to ensure that research subjects are protected. Saying that "the pressure the investigators...in New York State are under is regrettable and...unjust," Pruitt added that the public needs to be educated about the importance of these studies in order to build support for them.
"Women, children, minorities and the elderly are now stepping forward and saying, 'We have particular, very important health care issues that we want answered,'" Pruitt said.
He also noted that in order to answer those, researchers have to put together credible scientific projects. Once the studies are approved by government and local oversight groups, he said, "Those investigators must have the confidence that they can carry out research and not be second-guessed several years down the road."