Drug Trial Registry Called for in Wake of Antidepressant Findings: Known Suicide Risks Were Unpublicized

Kim Krisberg

Nations Health. 2004;34(9) 

Health advocates are calling for the creation of a national clinical trials registry after a series of studies and events on the issue of antidepressants showed that negative drug trial information is sometimes concealed from the public.

The call for such a registry followed news that drug manufacturers hid negative study results that linked antidepressant use in children to increased suicide risks. At a September hearing before the House Subcommittee on Oversight and Investigations, Ronald Davis, MD, speaking on behalf of the American Medical Association, called for a federal registry in which trials are "registered when they are begun, so that essential details are made public from a trial's inception, rather than from publication many years later."

According to the American Medical Association, industry-funded studies that have positive results are more likely to be published, and other factors, such as trial design, can skew the results of a drug study toward positive outcomes. However, a national registry that vigorously compels disclosure from the onset could prevent design factors that result in faulty study outcomes. Although a 1997 act of Congress established an online registry -- found at www.clinicaltrials.gov -- taking part in the registry is not a mandatory requirement and many industry-sponsored trials are not submitted at all. In the antidepressant case, not only did pharmaceutical companies withhold negative trial information, but the U.S. Food and Drug Administration is accused of taking part in suppressing such data.

"People need good information and doctors need good information," Janell Mayo Duncan, legislative and regulatory council for Consumers Union, told The Nation's Health. "When bad information is buried and good information is touted, it's really a great disservice to the public."

To compel submission to a federal registry, the American Medical Association recommended that Institutional Review Boards, which monitor biomedical research involving human subjects, require registration as a condition of approval. The association also recommended that registration information include sources of trial funding and contact information for those responsible for the trial.

To promote public disclosure, the International Committee of Medical Journal Editors in September announced that it will require "as a condition of consideration for publication, registration in a public trials registry." The committee, which includes publications such as the Journal of the American Medical Association and New England Journal of Medicine, will require the registry to meet specific criteria, such as being managed by a non-profit organization and accessible by the public for free.

On Oct. 15, following the advice of two of its advisory committees, FDA ordered that all antidepressants carry a "black box" warning label -- the most serious type of prescription warning -- that cautions that such drugs are linked to increased suicide risks among children and adolescents.

According to testimony from Robert Temple, MD, director of the Office of Medical Policy at FDA, presented before a congressional hearing on antidepressant use in children, the agency began reviewing studies in June 2003 that suggested the antidepressant Paxil increased risk of suicidal thoughts in children. FDA's move followed an application submission by the drug manufacturer GlaxoSmithKline seeking approval for the use of Paxil in children. After being asked to reanalyze its Paxil data for adverse effects, the drug company submitted a report to FDA in May 2003 showing "an increased risk of various thoughts and behaviors coded as events considered 'possibly suicide related,'" Temple testified. In reaction to the drug company report, British health authorities issued a public statement that Paxil not be used in children younger than 18. FDA officials ordered an internal review of the study and issued a public health advisory.

In February 2004, FDA's own internal review also showed increased risks of suicidal behaviors and recommended regulatory action, however, agency officials decided not to officially discourage the use of antidepressants in children at that time. The agency also decided not to present the report in full to its advisory committees studying the issue. Instead, in March, FDA called for stronger warning labels for a number of antidepressants that urged close observation of patients treated with such drugs. In mid-September, the agency's Psychopharmacologic Drugs and Pediatric Advisory committees released several new recommendations, including the black box label recommendation.

In the midst of FDA's work, an April study in the British Medical Journal reviewed six published trials of antidepressants paid for by drug companies. The authors found that the study results exaggerated positive results while downplaying adverse effects. The study also found that study subjects using antidepressants did not gain a "statistically significant advantage" over those using a placebo. In fact, in June, New York Attorney General Eliot Spitzer sued GlaxoSmithKline for concealing information about Paxil from doctors. The suit alleged the company, beginning in 1998, actively engaged in hiding negative information on Paxil's use in children. As part of the suit's settlement in August, the company agreed to publicly disclose clinical studies and pay $2.5 million to the state of New York.

More recently, in September, the drug company Merck pulled its highly popular drug Vioxx, a pain medication, from store shelves after recent studies showed the drug had adverse cardiovascular effects. However, the company knew of a study conducted almost four years ago that found Vioxx substantially increased heart attack risk, yet continued to market the drug directly to consumers, according to Public Citizen. Merck even received a warning letter from FDA in 2001 admonishing the company for minimizing such risk information in advertisements.

"The unknown is, once we require that all clinical trials be registered, will physicians behave any differently?" asked Arthur Levin, executive director of the Center for Medical Consumers. "These drugs will still be promoted to physicians and the public directly."

Levin said patients need more balanced drug information, and that means putting negative risk information up front so people can protect themselves from harm. "This is a society that tends to take a lot of drugs and has a favorable attitude toward drugs and there's no evidence that people are being scared away," he told The Nation's Health. "But, it's up to the physician to make the case that a drug should be used by a person -- that the benefits outweigh the risks. You can't do that by hiding the truth."

But some mental health advocates are worried that all the attention to the possible negative side effects of antidepressants might scare parents whose children would benefit from such treatment.

"Our position is that we want to do everything we can to protect children and families and to make sure the treatments they get are safe and effective," said Cynthia Folcarelli, executive vice president of the National Mental Health Association. "At the same time, we're concerned that the worst possible outcome of this debate...is that parents of kids who have signs of depression will be afraid to seek help."

Every year, 500,000 adolescents attempt suicide, and that doesn't even include all those who just think about it, Folcarelli told The Nation's Health. Adolescent depression is a serious public health problem, she said, and children who exhibit signs of depression should seek treatment. Folcarelli said she is also concerned that children are being given drugs for the wrong symptoms, as incorrectly evaluating children's mental health is a common problem.

"We really have a children's mental health crisis in this country," she said. Deborah Cross, MD, vice president of the New York State Psychiatric Association, agreed with Folcarelli, and said she is worried that if providers are reluctant to treat patients with anti-depressants, there could be an increase in suicides.

"We want there to be careful and thorough study of the problem, but we also want to make sure that people do not overreact, for example, by banning these medications," Cross told The Nation's Health. "These medications are lifesavers for some people." Nevertheless, all advocates interviewed by the The Nation's Health supported an open and transparent clinical trials registry with the teeth to have an impact.

"This is an important public benefit, and it shouldn't be left up to the drug companies," Levin said.

For more information on a clinical trials registry, visit www.ama-assn.org. For information on anti-depressants and children, visit www.fda.gov or www.nmha.org. For more news from The Nation's Health, visit www.apha.org/thenationshealth.

Nations Health. 2004;34(9) © 2004 American Public Health Association

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