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Experts weigh value of weight loss, new drugs against adverse events
FDA addresses issue by using a suicide scale to assess for psychiatric events in selected drug trials.
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A number of drugs in clinical trials and on the market have been linked to an increased risk for adverse psychiatric events.
2007 was marked by reports of mood disorders associated with popular drugs to treat epilepsy, seizures and smoking cessation. Last summer, the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) unanimously voted against recommending approval of rimonabant due to increased risks for suicidal ideation and behavior.
Rimonabant is a cannabinoid receptor 1 antagonist/inverse agonist that suppresses appetite and regulates food intake and storage of fat and sugar. It is marketed as Acomplia in Europe, and is manufactured by Sanofi-Aventis. After the EMDAC vote, Sanofi-Aventis withdrew its new drug application for the drug in the United States.
In an effort to monitor possible increased risks, the FDA has and is currently asking drug makers to include a comprehensive suicide assessment in clinical trials. The FDA would not reveal which manufacturers and clinical trials are using this assessment — it is an ongoing, evolving process, according to Eric Colman, MD, deputy director, division of metabolism and endocrinology products, FDA.
“The big question is which drugs will be assessed prospectively for suicidality and which drugs will not, and that is really just up in the air,” he told Endocrine Today.
 Clifford J. Rosen |
This is not a new rule, regulation, requirement or policy — the FDA has requested this information for certain drugs several times since 2001, according to an FDA spokesperson. In two cases, the Columbia Suicide Severity Rating Scale, used by the FDA and many other institutions, yielded information that led the FDA to list suicidality among the possible adverse events in the labeling of a drug.
“It is a case-by-case situation to draw the line,” Colman said.
The agency may ask for this information if there appears to be a class effect or if there are suggestive signals in early clinical trial data.
“When you talk about suicidality, completed suicide is the first concern, as that is the most serious outcome. Luckily, there have not been a huge number of completed suicides in these trials,” he said.
Discussion about new drug applications are by law considered to be confidential commercial discussions between the FDA and drug sponsors, and the FDA is held to confidentiality and trade secret rules, according to the agency spokesperson.
“[The FDA] does not want to approve drugs it feels are not safe, and yet it wants to be responsible to the people so that drugs needed on the market get on the market. It is a real catch-22,” said Clifford J. Rosen, MD, senior scientist at the Maine Medical Center Research Institute and acting chair of EMDAC during its meeting regarding rimonabant in June 2007. “But, if you try to appreciate what their mission is, it is really to protect the public first and foremost.”
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Photo by Bill Branson |
Suicidal ideation vs. weight loss
EMDAC determined that the risks associated with rimonabant outweighed its potential benefits. Findings from the RIO-North America trial revealed a 6.3 kg weight loss with the 20-mg dose compared with 1.6 kg with placebo; however, data presented to the committee also pointed to a 5.9% incidence of psychiatric adverse events among patients assigned to a 20-mg dose compared with a 2.1% increase with placebo, including depression, seizures, anxiety, insomnia and aggressiveness.
“There was some weight loss, but patients had to take rimonabant for the rest of their lives and, in that case, we had to be really sure about long-term safety,” said Rosen, also director of the Maine Center for Osteoporosis Research and Education Laboratory, St. Joseph Hospital.
An analysis by Robin Christensen, MSc, and colleagues published in The Lancet last year produced similar results to the findings presented at the committee meeting. Upon analyzing the four clinical trials in the RIO program, the researchers concluded that in comparison with placebo, use of rimonabant 20 mg was associated with a five times greater likelihood of at least 10% weight loss and a 2.5 times higher rate of discontinuation due to depressed mood disorders and anxiety.
Some argued that rimonabant had the same efficacy as sibutramine (Meridia, Abbott) and orlistat (Xenical, Roche) — the two currently approved weight-loss drugs — but resulted in more adverse events.
A spokesperson for Sanofi-Aventis said “we have been and continue to follow the recommendations of the FDA to further our understanding of the risk-benefit profile of rimonabant.” An extensive clinical trial program is underway that consists of a comprehensive program in more than 5,700 patients with type 2 diabetes. According to the spokesperson, Sanofi-Aventis plans to file for approval of rimonabant for use in diabetes and other areas in the near future.
Explosive risk factors
“The possibility of increasing the risk for psychiatric adverse events when using medications has been there all along, [but] nobody paid much attention to it,” Benedetto Vitiello, MD, told Endocrine Today. It has been well-established that certain drugs act on the brain, but the mechanism through which a drug increases suicidal ideation or behavior is unclear, according to Vitiello, chief of the Child and Adolescent Treatment and Preventive Intervention Research Branch, at the National Institute of Mental Health.
Vitiello stressed the importance of alerting clinicians and patients of the increased risks for suicide with certain drugs.
“Drugs cannot just be given in a vacuum — there should be some sort of education of the potential risks and attempts at following-up and monitoring for the emergence of possible adverse events,” he said.
There are a number of risk factors for suicide, including a past suicide attempt, depression, psychosis, family history of suicide, terminal illness and even having a close friend or family member commit suicide. Suicide can be contagious, according to Vitiello. These risk factors are “mechanisms that become explosive at some point,” he said.
“If a patient is already at high risk for suicide and there are alternative treatments, maybe it is a good idea to go with an alternative.”
Suicide severity rating scale
The Columbia Suicide Severity Rating Scale is “the gold standard for assessment in clinical trials,” according to J. John Mann, MD, who helped create the rating scale with a team at Columbia University. Variations of the scale have been used by the FDA and other institutions in antidepressant safety analyses and anticonvulsant trials.
 J. John Mann |
The Colombia Suicide Severity Rating Scale is an evolution of nearly two decades of work, said Mann, vice chairman for research, department of psychiatry, Columbia University Medical Center.
“It grew out of the concern for antidepressants but it became clear that other medications may have effects on mood and predisposition of suicidal ideation and suicidal action,” he said.
The scale uses direct yes or no questions, such as “Have you ever tried to harm yourself in order to end your life or because you wanted to die/kill yourself?” and “Have you actually had thoughts of killing yourself?”
“It has become increasingly more apparent that suicide is a risk and may be affected by medications, in a positive way or a negative way,” Mann said. “This has all led to an awareness that we have to quantify suicide risk in double-blind studies.”
However, assessing suicidal ideation is particularly difficult.
“It is hard to gauge correlations between what people say and what they do,” Rosen said.
According to Mann, the challenge is that most people with even major depression never attempt suicide.
“Clinically, for every person you pick up with these assessments that might be at risk for suicide or serious suicide attempts, you also detect a number of people who will actually never make a serious suicide attempt,” he said.
Clinical screening has traditionally involved good sensitivity but poor specificity, and the Columbia group is working to improve the specificity of the screening tools, according to Mann.
Since 2001, many other groups have adopted the questionnaire, which has been translated into nearly 100 languages.
Future of weight loss drugs
George A. Bray, MD, said he has never met an obese person who actually wanted to be obese.
“When they’re not obese anymore, they will tell you that they never want to go back to that stage,” he said in an interview. Bray is a Boyd Professor, Pennington Center, Louisiana State University and a member of Endocrine Today’s Editorial Board.
 George A. Bray |
“There is a lot of interest in having an effective drug on the market, which is something we do not seem to have at the moment. I wish I could say there was something great out there but there is not,” said Bray. He referenced sibutramine and orlistat and said that unfortunately, their sales have not been high due to a lack of significant weight loss with treatment.
Currently, there are hopes for Merck’s investigational weight-loss drug taranabant. The 52-week results of a two-year phase-3 study were presented at the American College of Cardiology 57th Annual Scientific Sessions held in Chicago in late March.
The newly released data indicated statistically significant weight loss with taranabant in combination with diet and exercise compared with placebo (6.6 kg vs. 2.6 kg). More than two times as many patients treated with taranabant 2 mg lost 5% of their body weight compared with placebo (57% vs. 27%) and more than three times as many lost 10% (28% vs. 8%).
Although the most frequent adverse events were gastrointestinal (42%), patients taking taranabant had a higher incidence of psychiatric adverse events (28% with 2 mg; 40% with 4 mg; 38% with 6 mg; 20% with placebo).
“Based on the benefit-risk considerations and the lack of a substantial improvement in the efficacy of taranabant at the 4 mg and 6 mg doses seen in our clinical program compared to the 2 mg dose, we have decided to evaluate taranabant in doses up to and including 2 mg in our phase-3 studies,” John Amatruda, MD, vice president of clinical research, Metabolic Disorders, Merck Research Laboratories, said in a press release.
Merck hopes to file for FDA approval of taranabant in 2008, according to a Merck spokesperson.
Taking into account the psychiatric adverse events that have been linked to weight loss drugs such as these, Bray said they may be beneficial only for a selected population (ie, patients with no personal or family history of depression).
“The current thinking about obesity is much like the thinking about hypertension,” he said. “You may not get the optimal effect with a single medication but by combining them you may get additional effects. But to do that you need to have more than one [approved] medication, and we are a little limited at the moment.” – by Katie Kalvaitis
Do psychiatric adverse events outweigh the potential metabolic effects of some drugs?
For more information:
- Addy C, Wright H, van Laere K, et al. The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metabolism. 2008;7:68-78.
- Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353:2121-2134.
- Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, FDA. Briefing document for the joint meeting. June 13, 2007. www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4306b1-fda-backgrounder.pdf.
- Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients. JAMA. 2006;295:761-775.