8/16/99

MEDIA CONTACT: Ruthann Richter, (650) 725-8047, (richter1@stanford.edu)

STANFORD ã An article in the Los Angeles Times has raised issues about a study, directed by a Stanford psychiatrist, involving use of the drug Depakote (divalproex sodium) in older youth incarcerated by the California Youth Authority (CYA). The drug, which has a long track record, is approved by the federal Food and Drug Administration for treatment of seizure disorders, manic depression and migraine headaches. It has been used in hundreds of thousands of children with seizure problems for many years with minimal problems. The drug was approved for treatment of manic depression, based on a large, multi-center trial that found it was more effective than the standard treatment, lithium carbonate, and was well-tolerated by patients. Preliminary studies also suggest that the drug may be effective in treating other psychiatric and medical conditions, including behavioral disorders such as aggression and agitation; the drug is often prescribed for these problems as well. Common side-effects of the drug include drowsiness, dizziness, gastrointestinal upset and diarrhea.

In 1996, Dr. Hans Steiner, professor of psychiatry at Stanford and a noted specialist in the field of adolescent psychiatry, sought to evaluate the effectiveness of the drug in preventing angry and aggressive outbursts and other uncontrollable emotions among the CYA youths. The goal was to reduce negative emotions, such as anger, and in doing so, to reduce reactive violence and crimes and improve the youthsõ involvement in school and other CYA programs. The study took a very conservative approach, comparing two relatively low dosages of the medication over a limited period of time (seven weeks). Steiner believed the drug could be potentially valuable to the participants while posing little risk to them. While Steiner guessed that the lower of the two doses might not be as beneficial, comparisons of dosage levels must be made in such controlled trials to determine efficacy as experience with other drugs has shown that medications are often effective at fractions of doses initially thought to be therapeutic. In his application seeking study approval, he noted that youth currently treated with the medication who have problems similar to those of the CYA wards "report increase in self esteem and well-being, especially when their mood improves. We expect similar results in this study."

The protocol for the study, a collaborative project with CYA researchers, was reviewed by the Stanford Human Subjects Committee in the spring and summer of 1996. The committee sought to ensure that there was low risk and potential direct benefit to individuals involved and that the study complied with federal regulations. Because the participants were incarcerated youth, extra steps were employed during the review process to ensure that additional safeguards were afforded to this special population.

Stanford officials also took the initiative to contact federal officials to ensure that the study and review process were in keeping with federal law. Kathy McClelland, Stanfordõs research compliance director, contacted the Office for Protection from Research Risks (OPRR) in the Department of Health and Human Services to obtain guidance on proper procedures to follow. She also spoke to officials at FDA, who indicated that an investigational new drug process was not required in this case. In addition, McClelland consulted with the attorney advisor for the Human Subjects Committee, who is on the staff of the universityõs Office of the General Counsel.

The Human Subjects Committee took a number of steps with regard to the study:

• It appointed an individual with special expertise related to prisons, who is a standing member of the committee, to review the study and serve as advocate for the incarcerated youth. In his report, the advocate concluded: "This proposal offers considerable potential benefit to the participants and to society. Since the risks are relatively low, the benefit-risk ratio is favorable."
• It requested an institutional review board at another medical institution to appoint an advisory committee whose members had relevant expertise to review the study and provide guidance. This advisory committee concluded that the study could go forward.
• It required a letter of approval from the CYA.
• It required the investigators to obtain written consent from the youths and permission from their parents.
• It required the investigators to find lay counselors who would be available to meet with the study participants. The participants could discuss any aspect of their participation in strict confidence with these counselors, who were part of the Foster Grandparent Program of CYA.
• It found that the study had the intent and probability of benefiting the participating CYA youth and approved it.

As to state law regarding prisoner research, the Committee requested that Dr. Steiner supply it with written approval of the study by the CYA. Dr. Dan Cashman, the CYA Medical Director, provided a letter of approval, which was relied upon by the Committee. The letter stated in part:

"In particular, the department appreciates your providing a formal evaluation about clinical treatment with the objective of reducing violence and recidivism.

"In the psychiatric treatment of Youth Authority wards provided by you and others that I have reviewed, treatment of Depakote is clinically appropriate for the purposes you describe. Your proposed treatment protocol will formalize our experience with this FDA-approved drug and make this medication available to wards who otherwise may not be so clinically treated."

State law also requires that a physician responsible for providing routine care for the youths be the primary person to supply the medication and monitor treatment. A CYA physician and a co-investigator on the study agreed with the expected benefits of the study to the participants. He selected the individuals for the study, performed their medical exams, explained the risks and benefits, obtained consents, prescribed the drug and monitored their physical and mental health throughout the study.

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