September 17, 2015
By Mark Terry, BioSpace.com Breaking News Staff
The British Medical Journal (BMJ) published an article yesterday that reanalyzed clinical trial data from then SmithKline Beecham’s Study 329, published in 2001. The original trial compared the efficacy and safety of paroxetine and imipramine with placebo in treating adolescents with unipolar major depression. The reanalysis, utilizing all of the clinical data, not just the published data, concluded that neither drug “showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs.”
SmithKline Beecham, now GlaxoSmithKline , published data from the clinical trial in 2001 in the Journal of the American Academy of Child and Adolescent Psychiatry. Its conclusions were that the drug paroxetine was safe and effective for adolescents. The drug was approved and marketed under the name Seroxat in the UK and Paxil in the U.S., and is still available, although a NICE guideline indicates it should not be used to treat depression in children and young people.
The original studies were conducted in the 1990s. Clinical studies on depression are difficult for a number of reasons. One is that anywhere from thirty percent to more than half of people receiving the placebo in trials improve. Another is, when evaluating whether there is a higher risk of suicide taking the pill, it’s important to remember that the patients were clinically depressed — is the suicide risk made worse by the drug or was the risk already there because of being depressed?
The original study, led by Martin Keller of Brown University, was published and SmithKline Beecham submitted that and other data to regulators in the U.S. and elsewhere. Scientists started criticizing the study almost immediately, arguing that the data was not convincing and that serious side effects had been underreported. Keller and his co-authors argued that testing of antidepressants at that time was in its infancy and that there was no bias. GSK backed the authors.
After that study, the use of antidepressants in adolescents jumped by 36 percent between 2002 and 2003. Regulators, concerned about the side effects, put black-box warnings on labels, which showed the sales of the drugs for children.
The new study, done in cooperation with GSK, which released all of its data — not all of which was available for review until now — was conducted by Joanna Le Noury at the School of Medical Sciences at Bangor University in Wales, UK, and other researchers from Emory University, the University of Toronto. They had access to literally thousands of pages of documentation from Study 329, including many that were previously confidential.
The authors found at least 12 out of the 93 adolescents who participated in the study had developed suicidal thoughts. “What would have happened if this data were available 15 years ago when the study was originally published?” said Peter Doshi, a BMJ associate editor and faculty at the University of Maryland School of Pharmacy to Reuters. “Would the black box warnings from the FDA have come earlier?”
This study is the first clinical trial analyzed under a BMJ initiative called Restoring Invisible and Abandoned Trials (RIAT). The project is an attempt to encourage drug companies to publish or correct misreported or abandoned drug trials. The goal is that physicians, researchers and regulators have complete and accurate information regarding drug safety.
“This reflects our commitment to data transparency,” GSK stated, adding that it promised to publish all study data, positive or negative, in the future. The company also noted that the drug Seroxat should not be prescribed to adolescents. “There is an increased risk of suicidality in pediatric and adolescent patients given antidepressants like paroxetine. This is widely known and clear warnings have been in place on the product label for more than a decade.”
In 2012, GSK pled guilty and paid a $3 billion fine for accusations that it had illegally promoted some prescription drugs, failed to report certain safety data, and its civil liability for alleged false price reporting. Paxil was one of the drugs cited in the case, stating, “from April 1998 to August 2003, GSK unlawfully promoted Paxil for treating depression in patients under age 18, even though the FDA has never approved it for pediatric use. The United States alleges that, among other things, GSK participated in preparing, publishing and distributing a misleading medical journal article that misreported that a clinical trial of Paxil demonstrated efficacy in the treatment of depression in patients under age 18, when the study failed to demonstrate efficacy.”
The new study further validates the claims of the U.S. Food and Drug Administration and overall industry concerns about data transparency in clinical trials.
