NYT
January 24, 2008

F.D.A. Requiring Suicide Studies in Drug Trials

By GARDINER HARRIS

After decades of inattention to the possible psychiatric side effects
of experimental medicines, the Food and Drug Administration is now
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. But since the
F.D.A.’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 F.D.A. 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 F.D.A. 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 F.D.A. 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.”

On Jan 24, 11:20 am, Lance  wrote:
> NYT
> January 24, 2008
>
> F.D.A. Requiring Suicide Studies in Drug Trials
>
> By GARDINER HARRIS
>
> After decades of inattention to the possible psychiatric side effects
> of experimental medicines, the Food and Drug Administration is now
> 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. But since the
> F.D.A.'s oversight of experimental medicines is done in secret, the
> agency's shift has not been announced publicly.
>
Thank you - this is an interesting article.

I don't understand why the FDA's rules should be secret. Surely the
access to information act should allow people to get hold of them.

It will be interesting to see what the results of these new trials
will be. Some drugs, like Ritalin, are, apparently, being prescribed
on an incredibly massive scale, so any effect is likely to have quite
far-reaching consequences.

thought godly, in conversation
with them, and sometimes only at the sight of them.

She had many extraordinary discoveries of the glory of God and Christ;
sometimes, in some particular attributes, and sometimes in many. She
gave an account, that once, as those four words passed through her mind,
wisdom, justice, goodness, and truth, her soul was filled with a sense
of the glory of each of these divine attributes, but especially the
last. Truth, said she, sunk the deepest! And, therefore, as these words
passed, this was repeated, truth, truth! Her mind was so swallowed up
with a sense of the glory of God's truth and other perfections, that she
said, it seemed as though her life was going, and that she saw it was
easy with God to take away her life by discoveries of Himself. Soon
after this she went to a private religious meeting, and her mind was
full of a sense and view of the glory of God all the time. When the
exercise was ended, some asked her concerning what she had experienced,
and she began to give an account, but as she was relating it, it revived
such a sense of the same things, that her strength failed, and they were
obliged to take her and lay her upon the bed. Afterwards she was greatly
affected, and rejoic