approached, I have given the view that the injuries in question have
not been caused by the SSRI. I have charged nothing for the great
majority of these reports, or nothing for any reports I have offered to
coroners' courts for the purposes of inquests.
http://www.springerpub.com/journalsamples/contra_Pfizer.pdf
ETHICAL HUMAN PSYCHOLOGY & PSYCHIATRY: AN INTERNATIONAL JOURNAL OF
CRITICAL INQUIRY
Volume 7, Number 3, Fall/Winter 2005
CONTRA PFIZER
By David Healy
Drug Administration' (FDA) Web site under the heading of documents
relevant to a then forthcoming Psychopharmacologic Drugs Advisory
Committee (PDAC) hearing on the use of antidepressants in children
(Ryder, 2004). FDA refused to post my response to the issues raised in
the Pfizer document. This response has been adapted for a freestanding
publication,
and may be timely in light of the fact that the FDA has scheduled a
further hearing on treatment-induced suicidality in adults for the fall
of 2005. In completing this piece, I remain heavily constrained by
confidentiality orders, and it can be noted that Pfizer has attempted
to enforce such orders vigorously by means of court action.
Pfizer's letter starts with a commitment to open debate. The letter
then seeks to attack my credibility in an ad hominem way rather than to
address the scientific issues. This attack comes despite the fact that
I have been previously invited by Pfizer to chair symposia for them, to
author articles for journal supplements for them, to give international
guest lectures for them, and to adjudicate on studies submitted for
Pfizer research awards
for them. Clearly, at one point Pfizer thought me a credible scientist
in the area of psychopharmacology."
More recently, however, when scientists from Pfizer have sought to have
me come and speak at forums, they have been told by their superiors
that this is not appropriate. Of even greater interest is that the
senior Pfizer physician representing sertraline at the September
hearings, Dr. C. Kremer, when working for another company had been a
key person supportive of my involvement as an expert witness in court
actions involving fluoxetine.
It has in fact been very difficult to get issues of suicidality and
psychotropic drugs debated in academic forums. In one of the few such
forums, at an Irish College of Psychiatrists meeting in 2003, my
understanding is that many clinicians and academics in the audience
were briefed by individuals linked to Pfizer and GlaxoSmithKline on
issues to raise with Healy. Many of these issues are reproduced in this
letter from Pfizer.
At other scientific meetings to which I have been invited to contribute
on these issues, such as the International Society of
Pharmacoepidemiology annual meeting, distinguished academics with links
to some of the major companies producing selective serotonin reuptake
inhibitors (SSRIs), who have never heard me present the data, it would
appear, apparently
sought to have me removed from the scientific program. Yet, when later
given the chance to challenge the points I make, they have failed to
ask me any questions in public.
I believe this effort to close down debate has little to do with the
scientific issues, in that my work on these points has been extensively
peer-reviewed and published in six different journals. I have taken the
unusual step of presenting many of these reviews, especially the
negative ones, on the Internet to make it clear where others differ in
their interpretations
of the data (Healy, 2004). I believe the issue has much more to do with
my temerity in being prepared to testify as an expert for plaintiffs.
Since my involvement as an expert witness, I have received documents
from at least one public relations company working for one of the
relevant SSRI companies that have listed me as a problem to be managed,
and I think what we are witnessing here is part of the management
strategy.
Before proceeding, it is worth putting the issue of expert witnessing
in context. In over 90% of the SSRI cases on which I have been
approached, I have given the view that the injuries in question have
not been caused by the SSRI. I have charged nothing for the great
majority of these reports, or nothing for any reports I have offered to
coroners' courts for the purposes of inquests.
Moreover, regarding actions by plaintiffs in general, far from being
plaintiff friendly, I have been used as an expert by the National
Health Service in the United Kingdom, and in that capacity have offered
reports favoring the defense rather than plaintiffs in, again, over 90%
of cases.
It should also be noted that I have no interests in any competing
treatments. I use antidepressants, including SSRIs, to treat both
adults and children, and, as a former secretary of the British
Association for Psychopharmacology, convened a consensus conference and
authored the ensuing guidelines on the issue of treating children with
psychotropic drugs (BAP, 1997). These guidelines endorsed the cautious
use of such drugs, a position I maintain to this day.
SPECIFIC RESPONSES TO PFIZER
In its July 2004 letter to the FDA, Pfizer made 12 points to which I
will respond.
First
First, the company claims its depression program has shown no evidence
of suicidality. In fact, Pfizer's depression program has a roughly
50% failure to demonstrate efficacy in clinical trials, and many of the
trials undertaken with Zoloft remain unpublished. So poor were the
results from the early trials that they raised concerns that this drug
might not get approved, as publicly available memoranda from Dr. P.
Leber to Dr. R. Temple indicate (Leber, 1991a, 1991b).
Zoloft, however, on the back of a selected set of published-only
studies, has been sold by Pfizer as an SSRI with unparalleled evidence
of efficacy. Arguably, there is a comparable discrepancy between the
claims made by Pfizer and the evidence base for those claims, and the
claims made for the use of Paxil for minors and the evidence base for
that use. The claims in the latter instance were characterized in June
2004 by the attorney general from
New York, Elliot Spitzer, as close to fraudulent. Regarding the
evidence for suicidality from the Zoloft studies, in over 20 cases
investigators have concluded that Zoloft has caused
suicidality/suicidal acts, and in more than 20 further cases, Pfizer
monitors overrode the judgments of the clinical investigators who had
not linked Zoloft to suicidality. These Pfizer personnel attributed
causality to Zoloft in the cases of these suicidality/suicidal events.
Given this, it is something of a mystery as to how Pfizer can claim
there is no evidence their drug causes suicide.
When data from the studies undertaken and submitted to FDA are analyzed
statistically, the point estimate for the odds ratio of suicidal acts
on Zoloft compared to placebo is greater than 1.0, which is indicative
of a risk, and probably greater than 2.0. Pfizer has sought to manage
this problem by a variety of methods, detailed below. The question of
what a point estimate greater than 1.0 means in the context of SSRIs
and suicide raises issues of interpretation that epidemiologists and
others interested in safety issues have to deal with. Many reputable
figures in these areas, including some working in the FDA, would argue
that the correct interpretation of a point estimate greater than 1.0 is
that given that this hazard is a potentially lethal one, it deserves
appropriate warnings and monitoring. ...cut....
Overarching Issues
The current crisis with SSRI agents has profound philosophical and
methodological underpinnings that deserve better than ad hominem
attacks. Current procedures to manage the entry of drugs onto the
market favor the detection of drug effects and are biased against the
detection of adverse effects. For instance, in order for a drug to be
licensed it has to show superiority to placebo in two controlled
trials. Companies, however, can run ten or more trials in carefully
selected samples using instruments carefully designed to pick up any
effect in order to demonstrate this, and even if the results show the
drug failing to beat placebo in the clear majority of trials, this is
not held against them. These other trials are commonly termed failed
trials rather than drug failures. This was a live issue in the
licensing
of Zoloft as the Leber memoranda outlined above make clear.
In contrast, the demonstration of a safety issue is not handled in this
way. In the case of safety, regulators only act if the overwhelming
preponderance of the data show a hazard. These differences in approach
have at their heart unresolved philosophical issues about the nature of
statistics. Safety data are typically presented in terms of confidence
intervals, so that, for instance, in recent antidepressant studies, the
rate of suicides on drugs compared to placebo is typically of the order
of two times greater but what is termed the confidence interval
surrounding this figure of 2.0 might be anything from .9 to 4.4.
There are two ways to interpret such a finding. First, according to a
school of thought stemming from R. A. Fisher, is the view that nothing
has, in fact, been shown unless the confidence interval does not
include 1.0-for instance, only a confidence interval that shows a
range from 1.1 to 4.4 for instance would be significant. Pfizer is
relying heavily on just this point to claim that it has not been proven
that Zoloft causes suicidal acts.
However, the Neymann-Pearson school of thought, and, in fact, the whole
point behind confidence intervals, argues that the best estimate of the
effect is 2.0, in this case, and that with a confidence interval of .9
to 4.4, while the data may be consistent with no effect, the scientific
data are also consistent with a 4.4-times increase in risk. The 2.0
figure is the one regarding which we can be most confident and is the
one that should dictate whether, for instance, warnings are placed on a
treatment.
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