Usually I cringe when I see yet another newspaper article about
suicide. But I always read them. This time, I did
cringe, but needlessly. The article turned out to be OK.
href="http://www.nytimes.com/2008/01/24/washington/24fda.html?ei=5090&en=69952ee3ab69a7b3&ex=1358917200&partner=rssuserland&emc=rss&pagewanted=print">F.D.A.
Requiring Suicide Studies in Drug Trials
By href="http://topics.nytimes.com/top/reference/timestopics/people/h/gardiner_harris/index.html?inline=nyt-per"
title="More Articles by Gardiner Harris">GARDINER HARRIS
January 24, 2008src="http://graphics8.nytimes.com/images/misc/logoprinter.gif"
alt="The New York Times" align="left" border="0"
hspace="0" vspace="0">
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...
All in all, I am not 100% sure that this new attention is a good idea,
but it probably is. The author is correct that the issue had
not gotten much attention until recently. If it weren't for
the news media, it would not have gotten as much as it has.
So it is good that the media have brought this issue into the
open.
There is a long history of links or potential links between medication
and suicide and suicide-related events. The oldest I remember
-- without taking the time to research it -- is the
title="FDA page"
href="http://www.fda.gov/cder/drug/InfoSheets/HCP/IsotretinoinHCP.htm">link
with
href="http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a681043.html"
rel="tag">isotretinoin (
href="http://www.rocheusa.com/products/accutane/" rel="tag">Accutane®).
There are many others, as mentioned in the article.
They include antidepressants, antiobesity agents, etc.
One of the lessons is that it is not possible to anticipate what drugs
might cause an increase in suicide and suicide-related behaviors.
At first glance, it is not at all obvious that a drug to
treat acne could do anything bad in the brain. That is one
problem. Similarly, it is not obvious that an antiobesity
drug could increase such a risk. Although, with
href="http://scienceblogs.com/corpuscallosum/2007/07/rimonabant_acomplia_problems_w.php">rimonabant,
at least there is a theoretical reason to anticipate such a problem,
based upon the drug's mechanism of action.
With antidepressants, the problem is different. On the one
hand, since the drugs clearly affect the brain, it is conceivable that
they could have such an effect. On the other hand, it seems
counterintuitive that a drug used to make a particular symptom go away,
could actually cause the same symptom to appear.
What this tells us, is that intuition is not a good guide for
anticipating possible adverse effects from medication. So, it
might make sense to establish routine screening.
Are there any potential problems? Yes, of course.
The most obvious potential problem is that it is not clear
that we have a good way to detect this risk. And once
detected, the risk must be quantified. Then you have to
figure out whether the numbers are significant. This is not
as simple as it may seem.
There are two risks here. For one, it is possible that the
screening method could miss some real risks. Studies done
before a drug is marketed typically are done on a few thousand selected
patients. It is easy to miss a real risk in that context.
This could give a false sense of security. Second,
it is possible that a drug could have no risk, yet a statistical
anomaly could falsely indicate the presence of a risk.
Chasing this down could greatly increase the cost of drug
development. It also could, potentially, cause a good drug to
fail to make it to the market.
href="http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a699062.html"
rel="tag">Ziprasidone (
href="http://geodon.com/" rel="tag">Geodon®)
ran into some problems when it was thought that there could be a
problem with Q-T interval prolongation. That turned out to be
minimally significant.
href="http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a697009.html"
rel="tag">Mirtazapine (
href="http://www.remeron.com/?OrgDom=remeron.com" rel="tag">Remeron®)
ran into some trouble because three patients had neutropenia in
premarketing studies. That turned out to be insignificant.
Yet, premarketing studies on
href="http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a689006.html"
rel="tag">fluoxetine (
href="http://prozac.com/index.jsp" rel="tag">Prozac®)
indicated a 1.9% incidence of sexual dysfunction. That number
turned out to be too low, by at least an order of magnitude.
So there are all kinds of problems with premarketing studies.
False positives and false negatives occur fairly often.
What this means, is that it is important to be selective about the
studies that you choose to do, because imperfect studies can cause more
trouble than they fix. So although it sounds like a great
idea to screen new drugs for their potential to cause an increased risk
for suicide and suicide-related events, I would not jump to that
particular conclusion. Rather, I would want to see to careful
consideration or the risks and benefits. There can be risks
inherent in the process of screening for risk.
Without the benefit of inside information about the process the FDA
went through, I do tend to think that they made the right decision.
The problems with false positives and false negatives are
well known. People in the industry and in the government have
been struggling with these problems for years. I assume they
know what they are getting into. Plus, the only way to get a
handle on a problem is to study it, even if there can be problems with
the studies. With care, the methodology improves over time.
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