The new rules represent one of the most profound changes of the past 16 years to regulations governing drug development. But since the FDA’s oversight of experimental medicines is done in secret, the agency’s shift has not been announced publicly.
The drug industry, however, is keenly aware of the change. Makers of drugs to treat obesity, urinary incontinence, epilepsy, smoking cessation, depression and many other conditions are being asked for the first time by the drug agency 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 federal 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 Columbia University’s department of psychiatry, led by Kelly L. Posner, to reanalyze the drugs’ clinical trials. This work caused 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 the French drug giant, Sanofi-Aventis. As agency medical reviewers pored over the drug’s clinical trial data, they discovered hints that it could cause psychiatric problems, too.
Unsettled by their experience with antidepressants, agency reviewers again mandated the use of Dr. Posner’s system. The assessment found that the drug doubled the risks of suicidal symptoms. In June, an F.D.A. advisory committee voted unanimously that the agency reject rimonabant because of its psychiatric effects, and Sanofi-Aventis withdrew the application although the drug is sold in Europe.
Just this month, the results of a trial of Merck’s obesity drug, taranabant, were published showing similar psychiatric problems. Meanwhile, 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 drug 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 P. Laughren, director of the drug agency’s division of psychiatry products. “So various groups within F.D.A. are now looking at suicidality more broadly as a possible adverse event.”
The drug agency’s 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 R. Insel, director of the National Institute of Mental Health.
Some critics say that the agency’s new-found focus on psychiatric side effects is long overdue.
“The list of drugs that causes psychiatric problems is a very long one,” said Dr. Sidney M. Wolfe, director of Public Citizen’s health research group.
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 in millions of patients.
Some drugs cause depression so often that doctors prescribe antidepressants prophylactically with them.
Among medicines still for sale, the FDA has determined that the drugs’ benefits outweigh their psychiatric risks. Still, the agency now wants to uncover such problems more reliably and before approval.
There are two reasons that the FDA 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 terms to describe depression or suicidal thoughts can vary widely, making them hard to discern.
“The whole spectrum of suicidal thoughts, ideation and attempts is much more difficult to define and study than” other drug problems, said Dr. Eric Colman, deputy director of the drug agency’s division of metabolic and endocrine products.
Indeed, the agency’s initial review of the effects of antidepressants in children was plagued by inconsistent and erroneous observations by investigators. A 10-year-old boy who tried to hang himself was listed only as having a “personality disorder,” an overdose of 11 tablets was called a “medication error” and a girl who slapped herself in the face was labeled as having attempted suicide.
Dr. Posner’s team spent months reclassifying these events as either a suicidal symptom or not. The team created a detailed questionnaire called the Columbia Suicide Severity Rating Scale, now adopted by the drug agency as an often mandatory test to be used in clinical trials.
The last time one medicine’s side effect led the FDA to broadly re-examine its drug approval process was in 1992, when it discovered that Seldane, a popular antihistamine, could cause dangerous heart arrhythmias. Tests revealed other drugs that could affect heart rhythms, and the agency soon mandated that nearly all experimental medicines be tested for heart rhythm effects.
Unlike the Seldane example, however, not every experimental drug program must use the new suicidal symptoms scale. Drug officials said that they looked at a drug’s molecular structure and its effects in animals before deciding whether to insist on the new test.
“That’s where it gets tricky,” said Dr. Colman. “It’s difficult to say where you draw the line.”
But Dr. Posner said in an interview that so many companies and academic research programs were adopting the suicide questionnaire that she was having trouble keeping up with the demand for its use. The questionnaire has been translated into 80 languages, and Dr. Posner has trained scores of teams of investigators from around the world on how to use it. On Jan. 4 she lectured a group of investigators at Yale.
Benjamin A. Toll, an assistant professor in the university’s department of psychiatry, was in the audience and said he planned to use the Columbia questionnaire in a trial almost immediately.
“It’s much more detailed than what we were doing before,” Dr. Toll said. “We used to ask, ‘Are you feeling down? Are you feeling sad?’ ”
Dr. Colman said that the new questionnaire, while important, would not end the uncertainty around suicidal symptoms.
“If a drug makes people depressed but doesn’t make them suicidal, what do you conclude?” he asked. “There will always be some degree of uncertainty.”
Source: FDA Press Release
Gardiner Harris The New York Times Company
