David Healy MD FRCPsych. In Press in Greenslit,
N (Ed). Pharmaceutical Cultures: Marketing Drugs and Changing
Lives in the US Rutgers University Press.
27. Consider this excerpt from the 1993
FDA medical review of Janssen Pharmaceutical's application to
market the antipsychotic drug, risperidone (Risperdal): "We
would consider any advertisement, promotion or labeling for Risperdal
false, misleading or lacking fair balance under Section 502 of
the Act if there is a presentation of data that conveys the impression
that risperidone is superior to haloperidol or any other marketed
antipsychotic drug product with regard to safety or effectiveness"
28. The clinical trials undertaken by Janssen
with Risperdal prior to marketing had compared it to an older
antipsychotic, another Janssen drug, haloperidol. In a similar
way, all recently released antipsychotics, including olanzapine
(Zyprexa), quetiapine (Seroquel) and ziprasidone (Geodon), were
compared to haloperidol in key pre-marketing trials. All companies
used much the same dose of haloperidol—a dose that was no
more efficacious than lower doses of haloperidol but which did
cause more side effects. The company rationale for using haloperidol
was that haloperidol was supposedly the market leading antipsychotic
agent. Whatever the real rationale, it was generally accepted
at the time these trials were conducted that newer agents stood
their best possible chance of looking better in terms of key side
effects—or at least no worse (if compared to the doses of
haloperidol used in these trials).
29. The role of a drug regulator in addition
to gate-keeping the entry of a new drug to the marketplace is
to regulate any claims a manufacturer might make as regards a
new product in its advertising or in any statements its personnel
might make to doctors afterwards. This assessment by the FDA would
appear to produce problems for any company that might wish to
30. But regulators have no control over
what academics say in lectures, report in medical journals or
elsewhere. FDA in addition have no control over what assessments
these academics might make in their roles as experts called on
to contribute to an expert consensus on new versus older drugs.
Shortly after Risperdal was launched, it was being widely touted
by academics as superior to older antipsychotics on the market.
31. Aside from the perennial need to market
the product, the 1990s brought a new hurdle for drug companies
to vault. It was increasingly necessary to persuade clinicians
and pharmacists that a new drug should be listed on hospital formularies.
These formularies were created to ensure new agents would not
be used without good evidence of cost-benefit returns. The formularies
are notionally meant to be evidence based and cost-sensitive.
A certain amount of trade-off was likely—if a new drug cost
more but could show a real benefit over older agents it would
32. No convincing evidence has ever been
forthcoming that any of the new "atypical" antipsychotics
are superior to the older "typicals" in either safety
or efficacy. A study completed in 2003 by the VA hospitals compared
olanzapine (Zyprexa) and haloperidol both in terms of efficacy
and tolerability and found no difference between them; olanzapine
in this study, however, cost approximately 80 times as much as
haloperidol (Rosenheck, Perlick, Bingham et al 2003). Despite
this lack of greater efficacy, olanzapine has won a place on formularies
since its launch in 1996 to the extent that it has become the
most profitable antipsychotic in the world.
33. In the absence of clear evidence from
clinical trials sufficient to warrant claiming a new drug was
superior to an older drug, it would appear difficult to make the
extra step to advocating that the newer agent is more effective
to the point of warranting a potential 80-fold increase in expenditure.
Nevertheless, shortly after their launch, Risperdal and other
recently released antipsychotics were available on most hospital
formularies in both the United States and Europe.
34. Pharmaceutical companies have clearly
found methods of circumventing these difficult areas of marketing
terrain. Circumvention is achieved by recruiting senior academics
and institutions to their cause, by means of three stratagems:
consensus conferences, pharmaco-economic modeling, and ghostwriting.
35. Consensus conferences aimed at producing
guidelines for clinical practice came into existence in the late
1980s (Sheldon and Smith 1993). A range of bodies took up this
apparently academic development. Within psychiatry, groups such
as the British Association of Psychopharmacology and the European
College of Neuropsychopharmacology, for example, produced guidelines
on the treatment of a range of conditions from depression through
to schizophrenia. This may have happened in part in an effort
to establish a political profile. In a number of the organizations
that produced guidelines, the influence of key individuals with
links to pharmaceutical companies is apparent.
36. At the same time pharmaceutical companies
began to sponsor meetings aimed at producing expert consensus
on issues such as the appropriate use of medication in schizophrenia.
These company sponsored meetings have often resulted in products
that may appear almost indistinguishable from non-company sponsored
guidelines or algorithms. While this might be thought as an exercise
designed to confound the recommendations of independent committees,
in fact committees that should be independent have come up with
recommendations that barely differ from explicitly company-sponsored
37. Given the lack of evidence-base for
the superiority of the new antipsychotics, just how have all these
guidelines ended up endorsing newer, more costly agents over older,
less expensive, but equally effective ones? One such guideline
system, the Texas Medication Algorithm Project (TMAP), offers
one set of answers (Petersen 2004).
38. Risperdal was launched in 1994. TMAP
was instituted in 1995, initially funded by Janssen Pharmaceuticals
(Johnson & Johnson), the makers of Risperdal. Soon afterwards
it had attracted funding from all major pharmaceutical companies.
TMAP drew up a panel of consultants to produce an expert consensus
on the use of antipsychotics, and later on the use of antidepressants
and mood-stabilizers (Gilbert, Altshuler, Rego et al 1998). Most
had prior links to Janssen and the other major pharmaceutical
companies operating in the mental health field.
39. The first set of TMAP guidelines concluded
that the atypical antipsychotic medications Risperdal, Zyprexa
and Seroquel were the drugs of choice for the management of schizophrenia
(Chiles, Miller, Crismon et al 1999). A second set concluded that
newer patented antidepressants, such as the SSRIs, Prozac, Paxil
and Zoloft, were the drugs of choice for the treatment of depression
rather than older agents such as the tricyclic antidepressants.
Subsequently mood-stabilizers such as Depakote and Lamictal have
been endorsed over other treatments for bipolar disorder. In all
these instances, the claims have been that the new drugs were
safer, more effective and better tolerated than the older agents.
The expert panels then formulated a set of algorithms or care
pathways for the treatment of schizophrenia, depression and bipolar
disorder based on these guidelines.
40. In a number of US states, legislators
have the powers to rule that algorithms and guidelines such as
these must be applied in the care of any patients receiving treatment
in public facilities. The logic here is that evidence based guidelines
and algorithms, if they really do reflect reality, can be expected
to be cost-effective over time. The legislators faced with the
question of adopting the algorithm and guideline proposals in
Texas meet infrequently, are poorly paid and are intensively lobbied.
Not surprisingly perhaps, TMAP was administratively endorsed in
Texas, and as a result state hospital doctors were required to
follow its algorithms and use these newer drugs first.
41. Researchers linked to TMAP were also
able to access the records of patients in state facilities, including
prison hospitals and mental hospitals, and report on the cases
that appeared to do favorably. These surveys produced data supporting
the selection of Risperdal and Zyprexa, for instance, as first
line treatments for schizophrenia, and later the selection of
SSRIs or other newer antidepressants over older treatments for
depression. On this basis, the TMAP guidelines and algorithms
began to be referred to as evidence-based guidelines and evidence-based
42. A related panel formulated a set of
medication algorithms for children, which recommended new antipsychotics
and antidepressants, such as Paxil (paroxetine), for the management
of children's problems (Hughes 1999). In this case, not only was
there a lack of evidence for the superiority of the newer over
the older agents; there was essentially no evidence base for the
recommendations other than a set of then unpublished clinical
43. The TMAP algorithm and guidelines were
subsequently marketed to other states on the basis of the Texas
precedent and instituted by administrative decision in a number
of these other states also.
In this way a very few people had effectively paved the way for
the acceptance of these guidelines and algorithms in many states,
and produced a situation in which a growing cohort of patients
treated in the public sector end up being put on and maintained
on these drugs. It will probably come as no surprise that within
Janssen there was a special unit aimed at maximizing the effectiveness
of the companies marketing in the public sector.
FROM TMAP TO
44. While the TMAP process appears close
to egregious, something very similar happened within the socialized
system of medicine in Britain. In the first place, opinion leaders
in Britain were recruited to panels to produce evidence-based
guidelines for antipsychotics. The experts invited to such meetings
will have had no pressure put on them to come to a particular
point of view. All of the publications of clinical trial data
for antipsychotic drugs will have been made available to them
on request, and they will have been encouraged to be evidence
45. Again as with TMAP, the results, despite
the assessment of the FDA, which will have been unknown to any
of the participating experts, must have been gratifying to the
sponsoring company (Mortimer, Healy, Gray et al 1998).
The process involved no overt selling of named medications, but
rather a set of positions endorsing the use of antipsychotics
in monotherapy regimens, and in doses consistent with British
National Formulary recommendations, and in a manner that would
avoid precipitating acute treatment related side effects. These
positions along with exhortations to adhere to an evidence based
approach were considered by the company as an effective marketing
46. Subsequently, a National Institute of
Clinical Excellence (NICE) was set up in Britain with a brief
to make recommendations as to the most clinically effective and
cost-effective treatments for both physical and mental illnesses.
The NICE guidelines for psychiatric treatment are an essentially
similar creation to TMAP, and earlier UK based industry sponsored
guidelines: a consensus of expert views rather than evidence based
views. The process involves a small number of psychiatrists, psychologists
and other stakeholders in mental health such as psychiatric pharmacists
collating evidence, preparing draft reports and then sending these
to selected experts for comments. Decisions are reached not by
experiment or evidence but by agreement. The process will also
have to take into account prior algorithms, guidelines and Delphi
panel recommendations (see below). And finally, as has been pointed
out publicly by the World Health Organisation, the process operates
within the constraints of the unwillingness of pharmaceutical
companies to share the raw data arising from clinical trials (WHO
47. The upshot of this in the case of the
antipsychotics has been a set of guidelines indistinguishable
from the ones drawn up by TMAP, or by other guideline groups linked
closely to pharmaceutical companies (NICE 2003). NICE recommends
the use of the new antipsychotics over old, even though it acknowledges
it does so without having any evidence base for this. In fact,
the NICE guidelines fly in the face of evidence that new antipsychotics
compared in clinical trials with the older antipsychotics and
placebo produce significantly higher death rates from a variety
of causes and significantly higher suicide rates, as well as a
range of physical problems, from cardiovascular to endocrine disorders,
that were not linked as frequently to the older antipsychotics.
48. In a public health system such as the
NHS, NICE guidelines are implemented in a very similar way to
the TMAP guidelines. The medical directors of hospitals will ordinarily
seek to ensure that their clinical staff adhere to NICE guidelines.
As a direct result of NICE then a much larger number of patients
will end up being given new rather than old antipsychotics than
would otherwise have been the case, with a probable resulting
detriment in the collective patient health, brought about at vast
cost. It is all but impossible for individual clinicians to opt
out of the system as the public health system endorses adherence
to these guidelines and practicing outside the guidelines may
not be regarded as evidence based.
49. The critical influence here lies with
the clinical trials that supposedly form the basis for the guideline
process. Newer agents almost invariably have more and larger trials
than older agents, especially if this is for indications that
have been "created" since the older drugs went off patent.
A great number of older agents may in fact have minimal trial
data. Those constructing the guidelines rarely appear to take
into consideration the fact that the larger the trials needed,
the weaker the drug must be, and that in general trials are only
needed when there are some doubts as to whether the drug actually
works or not. But, even more critically, the underlying data that
might reveal increased deaths from suicide and other causes that
might occasion a different set of conclusions are never available
to those constructing the guidelines.
50. While the data that might have led NICE
to a different conclusion were not available in the reports of
randomized trials of these agents, a good deal of relevant data
was in fact publicly available in reviews published by the Food
& Drugs Administration (FDA) for each of the new antipsychotics
at the time of licensing. In the case of suicides, a great deal
of the data was available in a paper on rates of suicides and
suicidal acts in clinical trials with novel antipsychotics.
51. These published data show high rates
of suicide on Risperdal and perhaps the highest rates of suicide
in clinical trial history on Zyprexa (see table 1). But the most
surprising thing is that the paper offers no figures for suicidal
acts on Zyprexa, while it does offer figures for suicidal acts
in the clinical trials programs for the other new antipsychotics.
Against a background of possibly the highest suicide rates in
clinical trial history, this absence of data on suicidal acts
for Zyprexa is striking. Eli-Lilly, the makers of Zyprexa, have
since refused to answer questions as to what the rate of suicidal
acts on their drug might be. Despite this, this drug has become
the best selling antipsychotic on the marketplace.
52. NICE guidelines however as mentioned
endorse the use of both Risperdal and Zyprexa over older agents,
although given the absence of these key data and public knowledge
about this key absence, it is difficult to see how any patient
taking Zyprexa can be taking it on the basis of informed consent.
While NICE guidelines do not have the force of law, it would be
difficult for clinicians in the UK to flout this guidance. Thus,
there are good grounds to think that the availability of NICE,
TMAP and other guidelines has resulted in a vast increase in the
expenditure of drugs in the mental health domain at a presumptive
cost to the development of other services, and this increase has
also taken place without any reasonable expectation of health
gains at either the individual or systems level.
53. In the case of these newer agents, another
method resorted to by companies has been a set of pharmaco-economic
procedures. Pharmaco-economics as a discipline began in the 1970s,
heavily subsided by the pharmaceutical industry (Healy 1998).
It basically involves estimating and comparing the costs of leaving
a condition untreated against the costs of treatment. The original
view of the first pharmaco-economists was that the complications
of establishing treatment effects and outcomes for psychotropic
drugs across a range of domains of value in mental health meant
it would be impossible to apply the procedures of pharmaco-economics
to psychiatric conditions and treatments.
54. Nonetheless the emergence of a set of
SSRI antidepressants and atypical antipsychotics that could not
be distinguished from older agents in terms of efficacy or tolerability,
but which were associated with greatly increased costs, led to
a flurry of pharmaco-economic exercises. This is exemplified nicely
by the emergence of supplements to major journals detailing a
range of pharmacoeconomic approaches that probably did a good
deal to smooth the marketing path of the SSRI antidepressants
55. One of these methods involved the establishment
of Delphi panels of experts. Delphi panels invite experts to consider
clinical trial data and estimate the likely translation from the
actually published randomized trial evidence to possible outcomes
in clinical practice if the drugs are adopted widely. These outcomes
are then costed by economists working to the manufacturing company.
56. The participants in these exercises
will again be unaware of assessments such as those made by the
FDA, or the data on suicide or death rates from trial programs.
The invariable outcome of these proceedings has been sets of models
indicating that treatment with newer agents costing ten to eighty
times more than older agents would in fact lead to savings in
either for profit healthcare systems such as that of the United
States, or socialized medical systems such as the UK mental health
system (Guest et al 1996).
57. No one seems prepared to say what the
original exponents of pharmaco-economics realized, namely that
short-term trials cannot be used for this purpose. This issue
is now further complicated by something that would once have been
all but inconceivable, which has been hinted at above and is developed
below, namely, the fact that in a growing number of cases critical
aspects of the raw data are substantially at odds with the published
58. In the 1980s, pharmaceutical companies
began to outsource a range of functions, such as the running of
clinical trials and medical writing, to other companies. Medical
writing was outsourced to medical communication agencies. With
this development, the practice of ghost-writing academic articles
picked up pace. Ghost-writing involves medical writers writing
articles, which subsequently appear under the apparent authorship
of academics who might or might not have reviewed the piece before
publication; the ghost traditionally is the medical writer who
receives no credit for her input. For some time it was believed
that this form of medical communication was largely confined to
journal supplements or peripheral journals (Healy 2003, &
2004). The first hints that the picture might be somewhat different
came in the mid-1990s. Flanagin and colleagues for example reported
in 1998 that up to 11% of articles published in six mainstream
peer reviewed journals involved the use of ghostwriters (Flanagin,
Carey, Fontanarosa et al 1998).
59. Recently a document became publicly
available covering the co-ordination during the course of 1998
of medical articles on Pfizer's antidepressant Zoloft (sertraline)
by a medical communications agency, Current Medical Directions
(CMD). This has permitted the comparison of published articles
written for Pfizer with other articles on Zoloft in terms of the
impact factor of the journals in which they appeared, prior publication
history of the respective authors and subsequent citation rates
of the respective series of articles.
60. The analysis showed the journals in
which Pfizer's articles were published had an impact factor three
times greater than the journals in which other articles on Zoloft
were published. The authors on Pfizer's articles had nearly three
times more previously published articles, as cited in Medline
and Embase, than the authors of articles not linked to Pfizer.
Of greatest importance was the subsequent citation rate. It might
be thought that, despite publication in the most prestigious journals
and under the apparent authorship of the most distinguished academics,
clinicians and researchers would find this literature too obviously
industry linked and would not be influenced by it. However, the
subsequent citation rates for the Pfizer-linked articles were
three times greater than that of the non-Pfizer articles (Healy
and Cattell 2003).
61. The profile of this so-called scientific
activity suggests that Pfizer ended up with a set of authors whose
background increased the possibility of the company's publications
appearing in the most prestigious journals. The combination of
distinguished journal, distinguished author, an efficient distribution
system and sponsored platforms appears to have led to an impact
on the therapeutics domain greatly in excess of 50% of the impact
of the rest of the literature on Zoloft. At present roughly three-quarters
of all randomized trials appearing in JAMA, NEJM or the Lancet
are industry funded.
62. The impact of this literature on third
party payers is at present unquantifiable, but authorship by perceived
opinion leaders with minimal company representation and non-declaration
of other authorship inputs increase the likelihood that these
articles will be influential with purchasers as well as prescribers.
63. Academics become opinion leaders in
a therapeutic field because they have their names on a larger
proportion of the literature appearing in the most prestigious
journals than their colleagues, and because they get asked to
international meetings to present this data (with which they may
not, in fact, have first hand acquaintance. This, allied to the
volume of industry-linked authorship, is arguably leading to a
situation in which the dominant figures in therapeutics actually
have little first hand research experience and may have no raw
data that they can share with others and probably have simply
never seen the raw data. This is a situation in which, in contrast
to the traditional perception of who the ghost authors are in
the medical literature, our leading academics have become ghosts
64. It is in fact a situation in which ghost-writers
increasingly have to take on ghost-acting as part of their repertoire.
This happens because the apparent authors of a study will often
now have so little familiarity or association with the basic data,
that they either cannot present it at major meetings or are not
inclined to do so in for instance poster form. As a result it
is becoming increasingly common to find medical writers presenting
posters at academic meetings, where they will in all probability
often be assumed to be doctoral students linked to the research
65. The situation that has developed underlines
the significance of the proprietary control of raw data. The raw
data from one trial of Zoloft compared to mianserin or placebo
in the CMD series, for instance, shows that one patient on Zoloft
committed suicide and three others had their treatment discontinued
because of increasing suicidal ideation. In contrast there was
just one case of emergent suicidality on the comparator drug mianserin
and no problems on placebo. But the final published article makes
no reference to any patient becoming suicidal in any way (Malt,
Robak, Madsbu et al 1999).
66. Second, within the CMD series of articles
on Zoloft, there were six that dealt with the use of Zoloft for
children. Of these six articles, only one mentions suicidality—one
single suicidal act. There were in fact six suicidal acts on sertraline
in the trials that these articles report: a rate approximately
six times higher than the published rate in adults.
The rate of suicidality in depressed children taking sertraline
was in fact nine per cent. However the article dealing with the
hazards of treatment in children who are depressed only reported
on the side effects that occurred at a ten per cent rate or more
(Alderman, Wolkow, Chung et al 1998).
67. The consequences of these developments
came to a focus in 2003 on the issue of treating children with
psychotropic drugs. The TMAP children's algorithm project outlined
above endorsed the use of SSRI antidepressants for treating childhood
nervous disorders, largely on the basis of a series of unpublished
trials. Although unpublished, the experts formulating algorithms
for TMAP and the experts running these trials and appearing as
authors on the few published trials were in many instances the
same people. These experts therefore had a better opportunity
to know what the raw data looked like than anyone else. As a result,
the issue of treating children with psychotropic drugs offers
a good case example to bring out a number of features of the new
world of manufactured consensus.
68. There has been a long-standing awareness
that it is difficult to show in clinical trials that antidepressant
drugs offer benefits for children. Despite this there were grounds
for using psychotropic drugs for children, and guidelines on the
treatment of children who were depressed endorsed such usage (Healy
and Nutt, 1998). The advent of the SSRI antidepressants offered
some hope that these agents might be shown to be effective for
children where efforts with older agents had failed.
69. In the early 1990s, regulatory authorities
approved the use of the SSRIs Paxil and Zoloft for the treatment
of depression for adults. They had previously approved Prozac
and subsequently approved Celexa and Efexor. From the 1990s, standard
letters of approval to companies noted that as these drugs were
likely to be used to treat children studies to establish the safety
of the drugs in these populations would be helpful. This encouragement
led to a series of studies of SSRIs in children during the early
to mid 1990s. A further incentive was put in place in 1998 with
an FDA Modernization Act (FDAMA) (Sharav 2003), which offered
patent extension on the basis of testing for rather than proving
safety; if the drugs showed hazards, the company still got patent
extension but had to incorporate this information in the label.
70. In the case of fluoxetine an early series
of clinical trials failed to establish efficacy for this drug
in treating childhood nervous problems. This work led to a study
that started in 1990, which involved extensive pre-screening of
patients so that less than one-fifth of those screened entered
the study, and those who did were put through a placebo washout
phase in an effort to reduce the high rate of placebo responsiveness
found in SSRI trials in children. Using these procedures, an article
that appeared in 1997 claimed that Prozac could produce beneficial
effects for children and adolescents (Emslie, Rush, Weinberg et
al 1997). However, in fact on the primary end-point measure, Prozac
was no better than placebo and on secondary measures benefits
were apparent on physician-based ratings but not on patient or
carer ratings. In addition, there was a 29% drop-out rate on Prozac
and the rate of behavioral side effects was greater on Prozac
than on placebo.
71. This Prozac study had been run under
the auspices of the NIMH. Subsequently another study funded by
the makers of Prozac, Eli Lilly, led to a comparable result (Emslie,
Heiligenstein, Wagner et al 2002). The second study, in contrast
to both the previous Prozac study and studies of other SSRIs and
in contrast to clinical practice, showed no greater rate of adverse
events on Prozac than on placebo. This combination of studies
led to a license for Prozac for the treatment of depression in
children and adolescents in 2003.
72. A further study had been undertaken
on Prozac for obsessive-compulsive disorder (OCD). This showed
somewhat more clearly positive results for Prozac over placebo,
but equally an excess of suicidality over placebo.
73. The first study undertaken with Paxil,
protocol 329, was conducted in the early to mid-1990s. The published
report from 2001 pointed to mixed benefits of Paxil on the primary
endpoints of the trial, with apparent responsiveness on some measures
accompanied by non-responsiveness on others, concluded that Paxil
is effective, safe and generally well-tolerated (Keller, Ryan,
Strober et al 2001). But in this study there was an increased
rate of suicidal acts on Paxil (5/93, a 5.4% rate) compared with
either imipramine (1/95) or placebo (0/89). The difference between
Paxil and placebo was close to significance at the 95% level (p
= 0.06), and the difference between Paxil and comparators (1/183)
74. These figures were not apparent from
the published the paper, where suicidal children were coded as
having had emotional lability. Hostility was also a reported side
effect in 6.5% of Paxil patients in this study versus 1.1% on
placebo. While the published paper does outline that emotional
lability might include suicidal acts, this is not a common meaning
of the term for most clinicians, who will be unaware that dictionaries
for coding side-effects, such as the ADECs system, offer the possibility
to code suicide, suicidal acts and suicidal ideation under the
heading of emotional lability. The same dictionary codes homicidal
acts, homicidal ideation and other aggressive acts under the heading
75. A second, protocol 377, and a third
protocol 701, and a fourth trial protocol 716 failed to demonstrate
efficacy for Paxil for depression, and also seem to have returned
an increased frequency of suicidality on Paxil. The first two
of these studies, which appear to have been completed by 2000,
were presented in part in abstracts in 2001 and 2002 that concluded
that Paxil was effective, safe, and generally well-tolerated (Wagner,
Wetherhold, Carpenter et al 2002). The fourth apparently
remained unscrutinized by FDA, when FDA undertook a review of
SSRI agents in children in 2003.
76. At much the same time studies of Paxil
in obsessive-compulsive disorder (OCD) were instituted, protocols
453 and 704. Reports of these studies in abstract form also claimed
that Paxil was effective safe and generally well tolerated (Geller,
Wagner, Emslie et al 2002). However, company data on file
point to an increased rate of side-effects on Paxil compared to
placebo, in the domains of hostility, agitation and hyperkinesis.
In 453, 6.3% of children taking Paxil (n = 97) became hostile
compared with 0% on placebo (n=100). In 704, 9.2% of children
became hostile on Paxil (n = 98) with 1% becoming hostile on placebo
(n = 105). There was also an increased frequency of suicidal acts
on Paxil (1/195) compared to placebo (0/205).
77. Finally, a study of Paxil was conducted
in social phobia, protocol 658. The unpublished results indicate
that Paxil might in some cases produce a beneficial effect in
children, but as with depression and OCD there was a higher rate
of adverse events in the behavioral domain on Paxil compared to
placebo. In this case there appear to have been three suicidal
acts in 165 children on Paxil compared to 0 in 157 on placebo.
78. In the case of Zoloft, in the mid-1990s,
a double blind placebo controlled study was undertaken in OCD,
which reported that Zoloft can have a greater beneficial effect
on core features of OCD than placebo (March, Biederman, Wolkow
et al 1998). This paper, which was one of the CMD series, noted
one suicidal act on Zoloft. A background expert report on the
study, however, points to two suicidal acts on Zoloft compared
with one that might have been on placebo.
In the absence of the raw data, it is not clear whether this suicidal
act on placebo actually occurred during the randomized phase of
the trial, as in the case of Pfizer's clinical trial program in
adults suicidal acts that occurred during the washout phase of
trials were coded under the heading of placebo (Healy 2003).
79. At the same time, Pfizer initiated open
trials of Zoloft in children who were depressed. In the first
of these, also reported in the CMD series of papers, 44 children
were given Zoloft of whom four became suicidal, a 9% suicidality
rate. The article reporting these results portrayed Zoloft as
likely to be effective, and generally well-tolerated; this article
also restricted itself to reporting on the side-effects that occurred
at a 10% rate or more (Alderman, Wolkow, Chung et al 1998).
A further open study of Zoloft in depression, also in the CMD
series, reported that there were three suicidal acts among 53
children who were depressed, a 5.6% rate (Ambrosini, Wagner, Biederman
et al 1999).
80. The expert report on these early OCD
and depression studies undertaken for Pfizer commented, "Clinical
studies in pediatric patients with OCD (aged 6-17 years) have
shown that sertraline is well tolerated. The adverse events which
led to discontinuation were generally psychiatric in nature, and
there were no discontinuations due to laboratory safety data following
administration of sertraline"
81. Subsequently, Pfizer conducted two randomized
controlled trials on Zoloft in depression. These were both negative;
combined, however, they were reported as showing Zoloft was effective
and well-tolerated (Wagner, Ambrosini, Rynn et al 2003).
In fact, 59% of children on Zoloft showed a change of 5 points
on a Clinical Global Impression scale against 49% of children
on placebo showing comparable changes, a finding that only reached
statistical significance when both studies are combined. In the
case of the side-effect profile, there was a doubling of the rate
of behavioral problems, including suicidal acts, suicidal ideation
and aggression in children on Zoloft (6/189) compared to children
taking placebo (2/187), and a 9% drop-out rate on Zoloft versus
3% on placebo for adverse events, but in fact 46 of 189 children
on Zoloft, 24%, dropped out for one reason or another (Garland
82. The actual drop-out rates on Zoloft
contrast with a lower rate of reported behavioral problems in
this study compared to earlier studies on both Zoloft and Paxil.
In addition it can be noted that the design in this study did
not encourage detection of adverse events. In SSRI studies where
side effects are more actively sought, the rates are higher. For
example, in a study of fluvoxamine in anxiety, increased motor
activity was found in 27% of children compared to 12% of placebo
patients (p=0.06) (Walkup, Labellarte, Riddle et al 2001). This
study in contrast to the Zoloft studies above used side effect
83. In the case of Efexor, two studies have
been undertaken in depression and two in generalized anxiety disorder.
One study published in 1997 suggests venlafaxine was safe, and
well-tolerated, but that efficacy had not been established (Mandoki,
Tapla, Tapla et al 1997). However it now seems that in
the combined depression studies there was an increased rate of
children becoming hostile (2% v < 1% on placebo) and suicidal
on venlafaxine compared to placebo (2% v 0%) (Kuslak 2003). There
seems no prospect that the full findings from these studies will
84. In addition to a small number of publications
(six full articles with three abstracts) from approximately 15
randomized trials in children, there were approximately 70 publications
of open studies or case reports with Celexa, Prozac, Paxil, Zoloft,
Luvox and Efexor. The open studies and published double blind
trials universally portrayed these drugs as safe, well-tolerated
and effective when given to children.
85. In 2002, the issue of Newsweek coinciding
with World Mental Health Day carried a cover feature of a depressed
teenage girl (Newsweek 2002). The inside story outlined
that there were three million depressed teenagers in the United
States, and that if left untreated this would lead to high toll
in substance abuse, failed marriages and careers and deaths from
suicide. The article noted that there were a number of new antidepressants,
such as Paxil, Zoloft and Prozac, which could help. Such articles
commonly have input from PR companies working to pharmaceutical
companies. The expectation in this case would appear to have been
that a number of SSRIs would shortly have a license to treat teenage
86. It is important to understand what licensing
means in this context. It does not mean that physicians would
thereafter be enabled to treat children who were depressed in
a way that they had been unable to do before. It means rather
that Pfizer, Lilly and Glaxo SmithKline would be enabled to convert
the vicissitudes of teenage angst into an illness, one supposedly
stemming from a chemical imbalance, and one that it was appropriate,
indeed almost morally necessary to detect and treat.
87. There are no grounds to believe that
NICE would have come to any different conclusions to TMAP on the
issue of how to treat depressed children, when they in due course
had gotten round to considering this issue, as they would have
been called on to do had the drugs been licensed in the United
Kingdom. Fate and the media intervened to ensure this never happened.
88. As a result of a Glaxo SmithKline application
to the regulators for a license for Paxil to treat childhood nervous
disorders, the raw data from clinical trials were lodged with
a number of national regulators. Within a fortnight of seeing
the raw data in response to queries as to the events behind the
term emotional lability, in May 2003 the regulators in the United
Kingdom issued a warning against the use of Paxil (Seroxat) for
minors. A few weeks later, Glaxo SmithKline wrote to all doctors
noting that Paxil use was linked to suicidality and that withdrawal
from Paxil was also linked to an apparent doubling of the rate
of suicidality. Three months later, Wyeth recommended against
the use of Efexor in children, in similar terms. Later that year
in December, the British regulators issued a position statement
in which they stated that none of these drugs, bar Prozac, had
demonstrated efficacy in depression.
89. These developments led to a projected
FDA hearing for 2 February 2004. Ten days before this hearing,
a working group for the American College of Neuropsychopharmacology
reported that after reviewing the evidence it was the task force's
view that SSRI drugs were safe and effective and well-tolerated
by children (Emslie, Mann, Beardslee et al 2004).
The authors of this report included Emslie, Wagner and Ryan who
had all been authors on study 329, and between had been authors
on most of the randomized trial literature on SSRIs given to children.
These three authors and their co-authors however noted that they
might not be correct in their conclusions that there were no problems
with SSRIs in that they had not seen the raw data.
90. Despite this move which was widely seen
as a pre-emptive strike, in February 2004, an FDA hearing on the
use of psychotropic drugs for children recommended strengthening
the warnings on these drugs, against a background of regulatory
assessments that at least 13 of the 15 studies undertaken of antidepressants
in children failed to show efficacy for the drug,
and panel views that there appeared to be an activation syndrome
on these drugs.
91. It transpired that in 1998, a SmithKline
Beecham assessment of the Paxil studies, which had been completed
at that time, 329 and 377, indicated that the drug did not work
for depressed children, but that the data would not be submitted
to the regulators, as a statement to the effect that the drug
had not been shown to work for children would have a negative
Selected positive data, however, would be progressed to publication.
92. What lessons can be drawn from this
situation which probably offers the greatest divide in all of
medicine between the raw data on an issue on the one side and
the published medical accounts purporting to represent those data
on the other?
93. First, this divide gives the lie to
a body of close to 100 papers and abstracts universally reporting
the benefits of these drugs. These open and randomized trials
it would seem have the appearances but not the substance of science.
The discrepancy between the papers and the underlying data may
stem from the possibility that many if not close to all of the
key studies have been ghost-written. It is difficult to avoid
such a conclusion when even the notional authors of the key papers
claim not to have seen the raw data.
94. It follows from this that it is almost
impossible to accept that these are scientific papers. What the
field would appear to need is a new term with which to designate
such infomercials, and a set of criteria that might reliably identify
this new genre of marketing product that aims at manufacturing
a clinical consensus. This it should be noted is the aim of all
good marketing—to own the market, not just to sell the product
95. A second point is that while pharmaceutical
companies know exactly how many prescriptions have been issued
and just what each physician writes, almost no-one knows how many
children or adults are on any psychotropic drugs. When this fact
is allied to the fact that serious adverse events are reported
by physicians to regulators in no more than one in one hundred
cases, a picture emerges in which Americans and others track the
fate of parcels put in the post 100 times more accurately than
they track the occurrence of adverse events on these drugs. The
quality of the information reported by patients on adverse events
indeed would appear to be much better than that reported by physicians
(Herxheimer and Mintzes 2004). This is a situation that could
not have been tailored better to maximize the consensus building
capacities of pharmaceutical companies.
96. There would appear to be reasonable
grounds to state that there must be some fundamental opposition
between marketing and science in that the former explicitly operates
to build consensus, while the latter supposedly moves forward
by fracturing consensus. When we have arrive at a situation in
which the mental sets of clinicians have been captured so that
it is difficult for them to conceive of alternatives to those
being sold to them, there are reasonable grounds to state that
such a field is no longer scientific. When there is almost no
possibility of discrepant data emerging to trigger a thought that
might be unwelcome to the marketing department of a pharmaceutical
company, these marketing capabilities would seem appropriately
described as totalitarian.
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154. Table 1:
INCIDENCE OF SUICIDES AND SUICIDE ATTEMPTS
IN ANTIPSYCHOTIC CLINICAL TRIALS DRAWN FROM REGULATORY LICENSE
Acts as %
The data here comes from FDA medical and statistical reviews
of risperidone, olanzapine, quetiapine and ziprasidone and from
Lundbeck pharmaceuticals in the case of sertindole. Analyzing
the data on suicides using an exact version Mantel Haenszel procedure
and a one-sided test for significance yields an odds ratio with
a Confidence Interval of (1.0825, Infinity), p = 0.03955, for
new antipsychotics compared to placebo.
Note: In connection with TMAP, this article has benefited hugely
by work undertaken by Allen Jones, Special Investigator in the
United States OIG Office of Special Investigations, detailed in
Dwight McKee and Allen Jones v Henry Hart, Sydni Guido, Wesley
Rish, Albert Masland, James Sheehan and Daniel P Sattele, CIVIL
ACTION No: 4:CV-02-1910, in the United States District Court for
the Middle District of Pennsylvania. Back
As of 2004, these guidelines had been adopted at some point by
Pennsylvania, California, Colorado, Nevada, Illinois, Kentucky,
New Mexico, New York, Ohio, South Carolina, Maryland, Missouri,
and Washington DC, or by jurisdictions within those states. Back
It is important to note that the author participated as a guideline
panel member in this Risperdal exercise. Back
It is important to note that the author also participated as
a Delphi panel member in this Risperdal exercise. Back
This claim is based on the personal experience and discussions
with ghost-writers/actors. Back
Pfizer. Sertraline hydrochloride for obsessive-compulsive disorder
in pediatric patients. Expert report. New York: Pfizer Inc., 1997,
Available on www.healyprozac.com. Back
Food and Drug Administration Review. Back
Data on File. Important Safety Information regarding Paxil in
Pediatric Patients, Glaxo SmithKline, Therapeutic Products Directorate:
TDP-Web, 18 July 2003. Health Canada, www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/paxil-pa-e.html Back
Data on File. Important Safety Information regarding Paxil in
Pediatric Patients, Glaxo SmithKline, Therapeutic Products Directorate:
TDP-Web, 18 July 2003. Health Canada, www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/paxil-pa-e.html Back
Pfixer Expert Report 1997. Sertraline hydrochloride for obsessive
compulsive disorder in paediatric patients. Approved 20 October
Pfixer Expert Report 1997. Sertraline hydrochloride for obsessive
compulsive disorder in paediatric patients. Approved 20 October
This was initially only available through GYMR, a Washington
based public relations company, who specialise in translating
the language of science and medicine into the more understandable
language of health. From GYMR.com, GYMR was "founded in 1998
by a team of experts in healthcare and social change . . . [it]
offers clients marketing and communications expertise that strategically
support public policy goals . . . [clients] include many of the
nation's most respected associations, government agencies, pharmaceutical
companies, philanthropic organizations and health initiatives."
"Whether it's provoking action on a national health issue
or crafting an organizational image that appeals to internal and
external audiences, GYMR excels at designing and implementing
issue and image campaigns." "Our media events are successful
because we have a nose for news. We know how to take the language
of science and medicine and transform it into the more understandable
language of health. We advise clients of the best dissemination
strategy for their news and make sure that the message they deliver
is compelling, documented and contributes to other national dialogues
in a real and meaningful way." Back
Central Medical Affairs Team. Seroxat/Paxil. Adolescent Depression.
Position Piece on the Phase 111 studies. October 1998. SmithKline
Beecham Confidential Document, available from the author. This
is also available on the Canadian Medical Association Journal