U.S. orders drug-approval tests to check suicide risk
After decades of inattention to the possible psychiatric side effects of experimental medicines, the U.S. Food and Drug Administration is requiring drug makers to study closely whether patients become suicidal during clinical trials.
The new rules represent one of the most profound changes of the past 16 years to regulations governing drug development in the United States. But since the regulators oversight of experimental medicines is done in secret, the agencys shift has not been announced publicly.
The drug industry, however, is keenly aware of the change. For the first time, the agency is asking makers of drugs dealing with obesity, urinary incontinence, epilepsy, smoking cessation, depression and many other conditions to put a comprehensive suicide assessment into their clinical trials.
In recent months, the agency has sent letters - it would not say how many - to drug makers requiring that they use such a scale. Merck, Sanofi-Aventis and Eli Lilly are all using a detailed suicide assessment in clinical trials being conducted now.
The seeds for the new U.S. effort were planted four years ago with the discovery that antidepressants may cause some children and teenagers to become suicidal. Top agency officials at first discounted the finding but commissioned researchers from the Columbia University department of psychiatry, led by Kelly Posner, to reanalyze the drugs clinical trials. This work led the drug agency and its experts to view the risk as real.
Then it received an application for rimonabant, a much-heralded obesity drug developed by Sanofi-Aventis, the French drug giant. As agency medical reviewers pored over the drugs clinical trial data, they discovered hints that it could cause psychiatric problems, too.
Unsettled by their experience with antidepressants, agency reviewers again ordered the use of Posners system. The assessment found that the drug doubled the risk of suicidal symptoms. In June, an agency advisory committee voted unanimously that the regulator reject rimonabant because of its psychiatric effects, and Sanofi-Aventis withdrew the application, although the drug is sold in Europe.
Just this month, published results of a trial of Mercks obesity drug taranabant showed similar psychiatric problems.
Fears have grown that drugs used to treat epilepsy, seizures and mood disorders may have similar effects. An extensive examination of these medicines by the agency should be completed this year.
Suddenly, agency officials realized that multiple classes of medicines might cause dangerous psychiatric problems.
“Clearly we were somewhat surprised when this signal emerged in the pediatric antidepressant data,” said Dr. Thomas Laughren, the drug agencys director of the division of psychiatry products. “So various groups within FDA are now looking at suicidality more broadly as a possible adverse event.”
The agencys concerns are consistent with a growing body of research confirming that behavior is heavily influenced not only by genes but also by seemingly innocuous changes in body chemistry. Drugs not reaching the brain were once thought to be largely free of mental effects.
“One lesson from pharmacology is that you can see effects on emotion and cognition without the drug entering the brain if a drug leads to peripheral changes in” other chemicals that enter the brain, said Dr. Thomas Insel, director of the National Institute of Mental Health.
Some critics say that the agencys new focus on psychiatric side effects is long overdue.
“The list of drugs that causes psychiatric problems is a very long one,” said Dr. Sidney Wolfe, director of the health research group at Public Citizen, a consumer advocacy organization.
Medicines to treat acne, hypertension, high cholesterol, swelling, heartburn, pain, bacterial infections and insomnia can all cause psychiatric problems, effects that were discovered in most cases after the drugs were approved and used by millions of patients. Some drugs cause depression so often that doctors prescribe antidepressants prophylactically with them.
Among medicines still for sale, the agency has determined that the drugs benefits outweigh their psychiatric risks. Still, it now wants to uncover such problems more reliably and before approval.
There are two reasons that the agency for years was inattentive to the psychiatric effects of new medicines. First, distinguishing between mental problems that spring from a disease and those that result from its treatment is often difficult. For antidepressants, many researchers suggested that suicidal behaviors resulted because, as patients depression lifted, they suddenly had the energy to carry out previous suicidal thoughts.
Second, drug side effects are often first identified in clinical trials when multiple doctors treating hundreds of patients record similar problems in trial notes. But in contrast to such problems as rashes or liver toxicity, terms to describe depression or suicidal thoughts can vary widely, making them hard to discern.
