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Abstract and Figures

While much excitement has been generated surrounding evidence-based medicine, internal documents from the pharmaceutical industry suggest that the publicly available evidence base may not accurately represent the underlying data regarding its products. The industry and its associated medical communication firms state that publications in the medical literature primarily serve marketing interests. Suppression and spinning of negative data and ghostwriting have emerged as tools to help manage medical journal publications to best suit product sales, while disease mongering and market segmentation of physicians are also used to efficiently maximize profits. We propose that while evidence-based medicine is a noble ideal, marketing-based medicine is the current reality. KeywordsEvidence-based medicine-Marketing-Marketing-based medicine-Pharmaceutical industry-Olanzapine-Quetiapine
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From Evidence-based Medicine to Marketing-based
Medicine: Evidence from Internal Industry Documents
Glen I. Spielmans &Peter I. Parry
Received: 2 October 2009 / Accepted: 15 December 2009
#Springer Science+Business Media B.V. 2010
Abstract While much excitement has been generated
surrounding evidence-based medicine, internal docu-
ments from the pharmaceutical industry suggest that the
publicly available evidence base may not accurately
represent the underlying data regarding its products. The
industry and its associated medical communication
firms state that publications in the medical literature
primarily serve marketing interests. Suppression
and spinning of negative data and ghostwriting
have emerged as tools to help manage medical
journal publications to best suit product sales, while
disease mongering and market segmentation of
physiciansarealsousedtoefficientlymaximize
profits. We propose that while evidence-based
medicine is a noble ideal, marketing-based medicine is
the current reality.
Keywords Evidence-based medicine .Marketing .
Marketing-based medicine .Pharmaceutical industry .
Olanzapine .Quetiapine
The larger issue is how do we face the outside
world when they begin to criticize us for
suppressing data...
AstraZeneca publications manager in internal
email 6 Dec 1999.
According to conventional wisdom, we are firmly
grounded in evidence-based medicine (EBM). While
many forms of data, such as clinical experience, case
studies, and uncontrolled trials can provide useful
information regarding patient care, the randomized
controlled trial (RCT) reigns supreme. As RCTs allow
the direct comparison of drug and placebo or of
various compounds to one another, their rigor exceeds
that of other forms of research (Sackett et al. 1996).
As more and more RCTs are published in medical
journals, we gain a better understanding of what
works best. Interventions that fail to demonstrate
adequate efficacy and safety lose first line status and
are discarded over time. Patients, of course, benefit
immensely from this meticulous scientific evaluation
process, as they can rest assured that they are
receiving treatments that show the greatest benefit
and least risk. So the story goes. However, one could
argue that rather than EBM, we are actually now
entrenched in marketing-based medicine (MBM), in
which science has largely been taken captive in the
name of increasing profits for pharmaceutical firms.
The case for MBM is based on several factors, each
of which influences the knowledge and practice of
medicine, including: suppression and spinning of
Bioethical Inquiry
DOI 10.1007/s11673-010-9208-8
G. I. Spielmans (*)
Department of Psychology, Metropolitan State University,
1450 Energy Park Drive,
St. Paul, MN 55108, USA
e-mail: glen.spielmans@metrostate.edu
P. I. Parry
Department of Psychiatry, Flinders University,
Adelaide, Australia
negative data, ghostwriting, disease mongering, market
segmentation of physicians, and failure of regulatory
authorities and peer-reviewed journals (despite
increasing efforts) to police what, in the words of
Marcia Angell, former chief-editor of the New
England Journal of Medicine, is a broken system
(Angell 2008, 1069).
Richard Smith, former chief-editor of the British
Medical Journal, in a paper titled Medical journals are
an extension of the marketing arm of pharmaceutical
companiesdescribed the many and sophisticated ways
in which drug trial data can be manipulated. He said it
took almost a quarter of a century editing for the BMJ
to wake up to what was happening(Smith 2005,
e138). Such manipulation was indeed difficult to
discern in the past, but the release of internal
pharmaceutical industry documents has shed light on
how marketing has come to trump science (e.g.,
Applbaum 2008;Steinmanetal.2004).
These documents have been released by courts where
pharmaceutical companies have been subject to litiga-
tion from class action plaintiffs and government
prosecutors. They allow for close examination of many
practices that are not typically widely publicized.
Indeed, although many internal industry documents are
legally available on the internet, there are as yet few
publications in the biomedical literature based primarily
on internal industry sources. These internal documents,
as well as material drawn from other sources, provide
insight into the intersection between marketing and
science within the pharmaceutical industry. While the
documents examined in this paper reflect our
specialties in mental health, the manipulation of
drug trial data they expose are clearly not limited to
only this field, as evidenced by situations involving
medications for osteoporosis (Washburn 2005)or
non-steroidal anti-inflammatory agents (Ross et al.
2008;Smith2006).
Science as Marketing
Especially given the current focus on using evidence-
based treatments, it comes as no surprise that the
pharmaceutical industry values scientific data that
demonstrate efficacy and/or safety of their products.
These data are particularly valuable when translatedinto
articles in high impact peer-reviewed journals. A
pharmaceutical industry trade publication emphasized
this point. It mentioned that a good publication plan
targets such information toward highly reputable, peer-
reviewed journals (which are today viewed as the
single most trusted source of information by US
physicians, over that of continuing medical educa-
tion, thus enhancing its scientific imprimatur, while
building relationships with the journals and their
readership)(Scarpuzza undated). Similarly, one
memo from Pfizer asked What is the purpose of
publication?and responded with High quality and
timely publications optimize our ability to sell Zoloft
[the antidepressant sertraline] most effectively
(Clary 2000). The same document makes it clear that
the data from sponsored drug trials belongs to the
company and the purpose of data is to support, directly
or indirectly, marketing of our product(see Fig. 1).
PeerView is a company that provides various
services to the pharmaceutical industry, including ...
products that support publication strategy and other
commercialization processes for our pharmaceutical
and biotech clients. The CEO of PeerView stated
that ...most pharma and biotech companies recognize
the significant impact that the clear and consistent
publication of results will have on subsequent
commercialization efforts(Villarroel 2007, 2). An
Eli Lilly internal document refers to new strategic
planning for the branding of its antipsychotic drug
olanzapine (Zyprexa). The document states under
strategic imperatives,that a goal is to develop
scientific research and publication plan that enhances
credibility of the new brand positioning and enables
the achievement of the ideal positioning(Eli Lilly
2001a). To help meet this goal, it is mentioned that
the company should mine existing data to generate
and publish findings that support the reasons to
believe the brand promise(Eli Lilly 2001a).
Fig. 1 Excerpt from document regarding marketing of sertraline
(Pfizer)
Bioethical Inquiry
Science is clearly related to marketing goals, which
of course is not necessarily problematic. If a product
is supported by good data, then few would find it
unethical to disseminate such information. But what if
the science is not supportive; what if a drug does not
demonstrate efficacy or is dangerous? What if a
studys results do not jive with the brand promise?
Suppressing and Spinning Negative Data
While drugs still enjoy patent protection, pharmaceu-
tical companies typically provide the lions share of
the funding to investigate their products. Journal
articles that tout the positive features of a drug help
to keep product moving from pharmacy shelves. The
data which form the backbone of these articles is
controlled by the sponsor. It is well-known that
studies funded by a drug manufacturer are much
more likely to yield positive results than studies of the
same drug conducted by researchers not tied to the
sponsor (Lexchin et al. 2003). One main reason for
this finding is that drug manufacturers are under no
obligation to publish negative results. Indeed, if the
primary goal of publicly traded drug firms is to
maximize return to shareholders, it makes no sense at
all to publish results that cast a drug in a negative
light.
Quetiapine: Internal vs. Published Data
AstraZenecas antipsychotic drug quetiapine (Seroquel)
is one of a class of drugs known as atypical anti-
psychotics or second-generation antipsychotics. In
2000, data comparing quetiapine to haloperidol, an
older, generic antipsychotic, were presented at the
annual convention of the American Psychiatric Associ-
ation. In a press release, the author of the presentation
stated: I hope that our findings help physicians better
understand the dramatic benefits of newer medications
like Seroquel, because, if they do, we may be able to
help ensure patients receive these medications first
(Olson 2009). The presentation, in line with the press
release, shows that quetiapine possessed a statistically
significant advantage over haloperidol in inducing
treatment response among patients with schizophrenia.
These data were based on a meta-analysis of four
studies that compared quetiapine and haloperidol.
However, documents released by the company during
litigation suggest a quite different story. The results of
research comparing the two compounds are found in
an AstraZeneca document, in which it was concluded
that quetiapine possessed weaker efficacy than halo-
peridol (AstraZeneca 2000;seeFig.2). The company
document was produced in March 2000, two months
prior to the rosy presentation of quetiapinesefficacy.
An email regarding this data, from a publications
manager at AstraZeneca, stated in part: The data dont
look good. In fact, I dont know how we can get a
paper out of this(Tumas 2000;seeFig.3). The lead
researcher on the 2000 paper, when queried
recently by a journalist regarding the claim that
quetiapine is significantly superiorto haloperidol,
conceded that the claim was indeed an exaggeration
yet maintained that the data analysis was accurate
(Olson 2009).
AstraZeneca also commissioned a comparative
trial known as Study 15. In this trial, patients in
partial to full remission of schizophrenia were
randomly assigned to receive either haloperidol or
quetiapine. At the end of the one-year trial, patients
receiving haloperidol fared better in terms of symp-
tom ratings and had significantly fewer psychotic
relapses relative to patients on quetiapine. These
negative results were not published. Rather, as stated
in an internal email, cherry pickingoccurred
(Tumas 1999; see Fig. 4). On some measures of
cognitive functioning, quetiapine significantly out-
performed haloperidol, which was the basis for a
publication (Velligan et al. 2002). The abstract
included the statement: Treatment with quetiapine
at higher doses relative to haloperidol appears to have
a positive impact on important domains of cognitive
performance that have been found to predict role
function and community outcomes in patients with
schizophrenia(239). While the paper suggested the
likelihood of better community outcomes, it failed to
mention the increased risk of psychotic relapse and
the relatively poorer scores on symptom measures
compared to haloperidol. In an internal email two
other buried trialsare mentioned, in addition to a
third trial that was pending potential suppression at
the time of the message (Tumas 1999).
Antidepressants: Internal vs. Published Data
Such tactics are not unique to any individual
company; they are quite plainly widespread. Indeed,
Bioethical Inquiry
one investigator calls data suppression the dirty little
secretof medical research (Dawdy 2008). The
researcher, Erick Turner, led a team which compared
published trials of antidepressants versus their unpub-
lished counterparts. Pharmaceutical firms must submit
their clinical trial data to the Food and Drug
Administration (FDA) as part of their application for
approval for marketing the drugs in the United States.
Turners team examined the publication status of trials
submitted to the FDA for all antidepressants approved
by the agency from 1987 through 2004 (Turner et al.
2008a).They found that 97% of the trials in which the
FDA review found a positive outcome were then
published in a journal. Some trials yielded a ques-
tionableoutcome, in which the data on the primary
outcome was negative but some secondary measures
found the drug was efficacious. Half of the trials in
which the FDA review found a questionable
outcome were published and half were not. Of the
questionable outcometrials that were published in a
medical journal, all were written up as if the results
were positive. Only one-third of studies finding
negative results were published, and over half of
those were published claiming that the study actually
found positive outcomes.
How can a trial go from showing questionable or
no efficacy to a definitive statement of efficacy?
Various publications did the following: failing to
report data from all participants (those who dropped
out due to lack of efficacy or adverse events were
excluded), reporting data from only one site of a
multisite trial, reporting data for something called
an efficacy subset,which is an apparent euphe-
mism for scrubbing inconvenient data from the
dataset, and by switching primary outcomes post
hoc (Turner et al. 2008b). For each of the 12
antidepressants, at least one trial was unpublished or
at least one trial was published with conclusions
conflicting with FDA review of the data. Thus, one
cannot blame one or two bad apples,as it appears
data suppression is part of the industrys standard
operating procedure.
Fig. 2 AstraZeneca internal
meta-analysis of quetiapine
vs. competitors/placebo
Fig. 3 AstraZeneca email
regarding meta-analysis of
Seroquel vs. competitors/
placebo
Bioethical Inquiry
Along the same line, data were selectively published
regarding antidepressant use among children and
adolescents (Whittington et al. 2004). One notable
example is a study (known as Study 329) comparing
paroxetine (a serotonin-reuptake inhibitor antidepres-
sant, manufactured by Smith Kline Beecham (SKB)
which is now GlaxoSmithKline (GSK) under the brand
name Paxil), imipramine (an older, tricyclic antidepres-
sant), and placebo in the treatment of adolescent
depression. Study 329, sponsored by SKB/GSK,
was published in 2001 with a clear message stated
in the abstract: paroxetine is generally well
tolerated and effective for major depression in
children(Keller et al. 2001, 762). However, the
trial data indicated that the drug was neither
efficacious nor particularly safe.
How did this come about? During litigation, GSK
released documents concerning the study, which were
then compared with the published version. The study
protocol and its revisions named two primary out-
come measures but both failed to demonstrate a
significant advantage over placebo at study endpoint.
The original study protocol also had six secondary
measures, all of which likewise failed to show
efficacy. In the published version of the study, four
of eight measures were reported as positive (rather
than zero of eight)all were on measures not called
for in the study protocol or revisions, a classic case of
data fishing.
The study publication referred to six of 93
paroxetine participants compared to one of 87
placebo participants experiencing emotional labil-
ity,(a term used to describe suicidal ideation/
gestures). An internal company report of side
effects of paroxetine yields moreeight partici-
pants experienced suicidal gestures or deliberate
self-harm and seven cases of hostility on paroxetine
compared to zero on placebo. An earlier draft of
the results stated that worsening depression,
emotional lability, and hostility were considered
related or possibly related to treatment,yet the
published version claims that only one case of
headache was considered related to paroxetine.
Thus, a drug failed to demonstrate efficacy on all
eight pre-specified primary and secondary efficacy
measures, is related to more treatment-emergent
suicidal gestures and hostility, and yet is claimed in
apeer-reviewedjournaltobesafeandeffective
(Jureidini et al. 2008).
Internal discussion about whether the company
should even publish the study included an email that
read: originally we had planned to do extensive
media relations surrounding this study until we
actually viewed the results. Essentially the study did
not really show Paxil was effective in treating
adolescent depression, which is not something we
want to publicize(White 2001). Nonetheless, the
study was published and, in an internal document
distributed to all company representatives selling
paroxetine, was labelled a cutting-edge landmark
studydemonstrating REMARKABLEefficacy and
safety for the drug (Hawkins 2001).
Fig. 4 AstraZeneca email
regarding cherry picking
and suppressing data
Bioethical Inquiry
Ghostwriting
Publications provide important information regarding
drug safety and efficacy. These articles are probably
most influential when they are perceived as independent
from the drug company. A physician may view an
article with a corporate authorship line as biased yet
view the same article as more credible if independent
academic authors were listed as contributors. However,
academics are often busy with research obligations,
speaking engagements, teaching, administrative
duties, clinical work and other tasks and some are
not particularly skilled at writing. Ghostwriting
overcomes these limitations. A pharmaceutical firm
may design a paper in-house or contract with a
medical education and communication company
(MECC) to write a manuscript.
Writing Firms
One example is Sunvalley Communication (http://
sunvalleycommunication.com). Their website describes
several important services (Hofland undated). They
produce papers closely linked with brand strategies
and also create a publication strategy to align with
marketing strategyand tweaktheir message to
best suit the publication and target audience. This firm
also offers to compose papers for researchers and
graduate students based on an outline provided by the
researcherand its involvement can be strictly confi-
dential(Sunvalley Communication undated). Another
company, Dianthus Medical, receives key messages
from pharmaceutical clients and writes a manuscript
outline, which they recommend receives approval from
all authors who will be listed on the paper. They then
write the first draft of the paper, ensuring that your
message is communicated in the most effective way,
then pass it along for the clientsapproval.Revisions
are made and the paper prepared for submission to
the journal (Dianthus Medical undated). This com-
pany lists such pharmaceutical giants as AstraZeneca,
GlaxoSmithKline, Lilly, and Wyeth among its clients.
Sunvalley and Dianthus are but two of many such
companies; descriptions of similar firms have been
provided elsewhere (Sismondo 2007).
The process is relatively simple: A ghostwriter
includes messages to maximize the marketing power
of the publication while one or more honorary
academic authors lend their names, titles, and purported
independence to the paper (Moffat and Elliott 2007).
While the audience may look suspiciously on a paper
with an all-corporate authorship line, the presence of
an academic author lends the air of independence and
prestige, making the article appear more credible. The
academic authors may review an outline or draft, but
typically perform little writing. For example, an
internal Eli Lilly document discusses drafting a full
feature for reviewby an influential author or perhaps
having the author develop the article after reviewing
the outline provided by the company or its associated
writing firm (Eli Lilly undated-a).
Ghostwriting in the Antidepressant Literature
The prevalence of ghostwriting is obviously hard to
determine. A few studies have suggested that
approximately 10% of papers are ghostwritten, but
these are based upon self-report surveys, which
likely under-report the incidence of such behaviour
(Flanagin et al. 1998;Mowattetal.2002).
Through litigation, one research team gained
access to documents regarding the antidepressant
sertraline (Zoloft)remember that according to its
manufacturer, publications were primarily meant to
maximize sales of this drug. A MECC named Current
Medical Directions (CMD) contracted with Pfizer to
produce 85 publications regarding the drug. Accord-
ing to one analysis, between 18% and 40% of articles
on sertraline from 19982000 were managed by
CMD (Sismondo 2007). The majority of the CMD
articles featured academic authorsone author
appeared in 12 such publications. In addition, the
articles managed by CMD appeared in significantly
higher-impact journals compared to non-CMD
articles on sertraline. One document from CMD
lists a number of sertraline publications in various
stages of completionseveral contain notes such as
Author TBD”—indicating that while a medical
writing firm was completing (or had completed) the
paper, a so-called authorhad yet to lend his or
her name to the piece. Other notes include such
comments as outline sent to Pfizer for approval
(Current Medical Directions 1999).
Researchers who investigated the CMD-affiliated
articles made the crucial point that traditional science
relies on authors having access to the underlying raw
data that forms the basis of publications (Healy and
Cattell 2003). However, publications written by drug
Bioethical Inquiry
firms or MECCs are often based on proprietary data
belonging to the drug firm. If an academic author
cannot vouch for the underlying data and did not
write the paper, then how can he or she be anything
other than window dressing for a marketing device
wrapped in scientific packaging? Healy and Cattell
(2003) note that a case of completed suicide and
several cases of suicidal ideation were not reported in
the CMD-authored pieces. The first draft of the paper
from Study 329, which clearly overstated benefits and
understated risks, was also written by a MECC
(McHenry and Jureidini 2008). The lead author of
the study said that he only reviewed data tables, not
the raw data (BBC 2007). Thus, honorary academic
authors are not just padding their vitae, they are also
potentially harming public health when they fail to
carefully review data presented in studies on which
their names appear as authors.
While honorary authors are typically affiliated with
universities, non-academic clinicians are also some-
times utilized to author papers in an unconventional
manner. GlaxoSmithKline used such a program to
promote its antidepressant paroxetine (Paxil). The plan,
which used the interesting acronym CASPPERCase
Study Publications for Peer Reviewhad the following
main goal: Publications of such articles will benefit the
sales force by expanding the database of published data
to support Paxil(SmithKlineBeecham undated). If a
physician mentioned a success with paroxetine, sales
representatives were to encourage the physician to
write a case study. Sales reps were instructed to
acknowledge the importance of the physicianstime
and offer to save precious time through the contracted
editorial staff, who could assist with everything from
literature searches to editing the paper. It seems that
physicians had relatively little leeway regarding their
papersone excerpt from a company document stated
that the editorial team would work closely with
contributing physicians to ensure rapid dissemination
of consistent data and messages.Itislikelythatdata
inconsistent with the companys marketing was not part
of the publication plan. At least five journals reportedly
published papers produced through CASPERR
(Edwards 2009a).
Placebo-controlled trials often include a placebo
wash-out phase, in which all participants initially
receive placebo prior to some participants then
switching to the drug under investigation. For
example, a study may use a 3-week period of
placebo washout, followed by 8 weeks of patients
receiving either drug or placebo. It should be
obvious that the comparison of efficacy and safety
between drug and placebo should begin during the
fourth week, when half of the participants have
started receiving active medication. Yet some
manufacturers of antidepressants counted suicidal
behaviour in the placebo wash-out phase against
placebo in their comparisons of drug to placebo.
Comparing suicidal acts on 11 weeks on placebo to
8 weeks on a drug helped to drive up apparent rates
of suicidal behaviour on placebo, which made the
drugs appear safe in comparison. Indeed, an article
was published in 1995 allegedly showing that
paroxetine reduces suicidality. The academic author
admitted that he had not seen the actual raw data;
rather, he had been provided data tables by the
manufacturer, which he then helped to convert into
an article (Glenmullen 2007). However, the data
in the article included suicide attempts which
occurred during the placebo washout phase,
though this was not stated in the manuscript.
GSK has since posted its own analysis online, in
which it notes an increased risk of suicidal
behaviour among patients taking paroxetine rela-
tive to placebo (GlaxoSmithKline undated). Nearly
anyone reading a journal article will assume that the
named authors had access to raw data rather than
misleading data tables provided by a drug firm.
While not technically ghost authorship, the manner
in which the data were translated into final form is
clearly outside of the norms of science.
Investigator-initiated Trials and Opinion Leaders
Further evidence on the extent that companies,
rather than honorary authors, own and manage drug
trial data comes from an internal AstraZeneca email
from the Global Brand ManagerSeroquel(que-
tiapine) to the SEROQUEL GLOBAL BRAND
TEAMdated 8/7/2003on the subject IIT
benchmarking report(Hagger 2003). IIT stands
for Investigator-initiated trialswhere an academic
or clinician from outside the company is sourced as
author of the trial. This email refers to a series of
interviews carried out with internal AZ staff who
were known to have worked for competitor compa-
nies before as well as a number of KOL [key opinion
leader] investigators from the UK, Italy, Germany
Bioethical Inquiry
and Spain.The email lists key messages emerging
from the report:
&...LillyrunalargeandhighlyeffectiveIIT
program...They offer significant financial support
but want control of the data in return. They are
able to spin the same data in many different ways
through an effective publications team. Negative
data usually remains well hidden.
&Janssen have a well organized IIT plan...no IIT
data is allowed to be published without going
through Janssen for approval, and communication
is controlled by Janssen. High expectations are set
on investigators who publish favourable results
but they are well rewarded for their involvement.
They seem less concerned than Lilly about
negative data reaching the public domain.
&BMS IIT program is growing very fast in launched
markets...most proposals are modified by BMS.
Strategic focus is unlicensed indications...
Recommendations...for AstraZeneca...publica-
tions should be more creative spinning the data,
aka Lilly...
In fact an Eli Lilly document on influencing key
playersin a passage headed Investigator-Initiated
Trials, Relationship Building, and External Authorship,
states:
Given our current business needs, it is important
that funds spent on IITs predominantly support
the brand strategy. The review process should
consider whether they are on strategy, as well as
looking at whether they fill current gaps in our
scientific data (Eli Lilly undated-b).
KOLs with the right message can be very valuable
to a company. An August 2002 email reporting on a
Janssen-sponsored dinner presentation on metabolic
side-effects of atypical antipsychotics in which a
speaker consistently implicated (Zyprexa) as a likely
cause of type 2 diabetes or cardiac problems via
weight gainnoted I think if I were with J [Janssen],
Id be throwing some cash at this chap to get his
message more widely known(Eli Lilly 2002a). The
Eli Lilly Key Player Playbookranks contracted
academic experts as Guild and Executive level
Thought leaderswho are well respected and
acknowledged by their peers...influence the thinking
and treatment practices of their peers...and are
typically in the academic setting and treat a minimal
number of patients, if any...and serve on academic
advisory boards, providing feedback to the Zyprexa
Product and Brand Team(Eli Lilly undated-b). Next
in rank are Consultant Thought Leaders...who are a
critical component of successful DTP (direct to
physician i.e. sales rep) interventions and stimulate
the physicians at both the regional and the local level.
A September 2000 letter from a psychiatrist who was
one of our (Eli Lilly) speakerson off-label use of
olanzapine by primary care physicians suggested the
local thought leader understood his role very well:
...Once the ground is extensively plowed with
good credible clinical information, not limited
by the GPP [Good Promotional Practice] guide-
lines that restrict information to schizophrenia
and acute mania, then (perhaps) turning the
sales force loose may be appropriate. I believe
one of my strengths is in taking scientific
information and placing it in a clear, clinically
useful format...Lilly could use someone with a
strong clinical background but with strong
marketing instincts to assist them on this one
(Eli Lilly 2000a).
Safety: Science or Marketing?
Weight gain, hyperglycaemia and precipitation of
diabetes have been major concerns in the side effect
profiles of atypical antipsychotic medications. Internal
company documents from Eli Lilly and AstraZeneca
have a significant focus on the marketing manage-
ment of these side effects.
Olanzapine: Managing Perceptions of Side Effects
The transcript of a speech by the olanzapine
(Zyprexa) Brand Manager stated: For Zyprexa,
weight gain is the ultimate topic to handle with skill.
Take this opportunity to tell the truth, to fight fire with
facts and to put this manageable side effect in
perspective. Keep it simple, so that you dont
overwhelm the doctor with data(Bandick 2001).
Industry documents, read as a whole, give a strong
impression that ensuring adverse events not over-
whelm the doctormeans telling the doctor the bare
minimum about them.
Bioethical Inquiry
Eli Lilly had been aware that forty percent [on
olanzapine] gained 7% body weight(the FDAslevel
of significant concernfor weight gain) from at least an
early trialthe HGAJ studyreported in minutes of a
meeting with the US schizophrenia advisory panel in
December 1995 (Eli Lilly 1995). The company received
a letter of reprimand from the FDA in November 1996
reminding that the information on weight gain was
indeed included in the approved labelling, but as an
adverse event, not a therapeutic benefit(Feather 1996).
An internal email among senior science executives in
Eli Lilly dated 24 November 1999, subject:
Olanzapine-associated Weight Changes (OWC)noted
that, ...OWC has been and continues to be a top
priority for the Zyprexa Product Team. The email went
on to state: Olanzapine is viewed to have more
associated weight gain than risperidone, seroquel, and
traditional neuroleptics (Fact: the order of weight gain
among antipsychotics is: Clozapine>olanzapine>
seroquel>risperidone>traditional neuroleptics). The
email noted Physicians want more databut also,
Blanket detailing will be damaging since many
physicians do not see OWC as an issue(Breier 1999).
Despite this early recognition that olanzapine caused
more weight gain than other antipsychotics apart from
clozapine, the marketing message for sales visits and
CME became the comparable ratesor class side
effectmessageolanzapine was no different than
other atypical antipsychotic agents in inducing weight
gain or diabetes (Eli Lilly undated-c; Eli Lilly 2000b;
see Figs. 5and 6). A September 2001 hyperglycaemia/
diabetes resource guide for sales reps states:
What do we mean by neutralizingphysicians
concerns about hyperglycemia and how do we
go about this? By neutralizing we mean level-
ling the playing field, setting the record straight
with the comparable ratesmessage (Eli Lilly
2001b).
Documents reveal Eli Lilly wanted to keep weight
gain and diabetes as separate issues that were not
linked. An undated review of Olanzapine core safety
and efficacy beliefsstated: A causal link between
Olanzapine therapy and diabetes has not been
established(Eli Lilly undated-d). However, the same
document also noted: A potential reason for this is
that most of our studies were not designed (especially
given the relatively short duration of these studies) to
study a link between Olanzapine therapy and Diabetes.
Documents reveal the company was in receipt of letters
from psychiatrists describing anecdotal reports of high
rates of hyperglycaemia and diabetes from olanzapine,
such as a letter dated 17 November 1999 stating: we
have had eight patients out of possibly 35 on Zyprexa
show up with high blood sugars...we certainly have
never seen this with Haldol, Navane, Risperdal, and
others to this extend [sic](Ventura County Behavioral
Health Department 1999). An early report of data on
adverse events from placebo-controlled trials of olan-
zapine stated in larger font than the rest of the
document:
As of September 30, 1999, olanzapine-treated
patients (N=4,234) who had no history of
diabetes mellitus and whose baseline random
plasma glucose levels were 140 mg/dL or lower
were identified. Random glucose levels 160 mg/
dL but <200 mg/dL (possibly hyperglycemia, not
necessarily diabetes) were observed in 2% of
Fig. 5 Eli Lilly instructions to sales reps regarding weight gain
issue
Fig. 6 Olanzapine diabetes sell sheet excerpt
Bioethical Inquiry
patients. Of these patients, the random elevated
glucose levels were found to be transient in 44%
while they continued to receive olanzapine.
Random glucose levels 200 mg/dL (suggestive
of possible diabetes) were observed in 1% of
patients. Of these patients, the random elevated
glucose levels were found to be transient in 26% of
them while they continued to receive olanzapine
(Eli Lilly undated-e).
In other words, despite the short-term nature of
most of these trials, 3% of patients were exhibiting
possible new onset hyperglycaemia or diabetes and a
proportion of them reverted to normal when olanza-
pine was withdrawn. The fact that hyperglycaemia
was reversible at least if caught early was not
appreciated by one Eli Lilly company psychiatrist,
who responded in an October 2002 email: But,
surely we want patients to stay on OLZ long-term, so
the reversibility of the event is not an advantage?
(Williamson 2002).
An internal email dated 12/01/98on Subject:
Re: Wishing/Goldstein articlesstated:
I do have concerns regarding making any
connections between olanzapine-induced weight
gain and hyperglycemia. Therefore, in my
opinion, I would not include your following
statement: Patients who gain weight may
develop insulin resistance which may lead to
hyperglycemia and diabetes(Kinon 1998).
By September 2000 Eli Lillysownmarket
research revealed that many more physicians (81%)
associated increased risk of diabetes with...Zyprexa
than with other agentsClozaril (56%), Risperdal
(16%), Haldol (11%), Mellaril (11%), Seroquel (7%),
Tercian (4%) (Phoenix International Research 2000).
An internal email to 15 company scientists and
executives from October 2000 on Subject: meeting
with endocrinologic consultantsnoted at least the
vocalendocrinologists were disputing the companys
finding that relative risk was not higher than
comparative drugsand reinforced (the writers)
impression that hyperglycemia remains quite a threat
for olanzapine and may merit increasing even further
medical attention and marketing focus on the topic
(Baker 2000). A reply email revealed a growing debate
within the company that unless we come clean on
this...issue that Zyprexa leads to diabetes...it could get
much more serious than we might anticipateand urged
gaining the ear of senior leadership and articulating this
finding(Brodie 2000).
Nonetheless the company still held to the marketing
strategy of comparable ratesand a December 2000
diabetes situation analysison Market Research on
message’” reported the comparable ratesmessage
appears to be generally believable, makes em think but
not all MDs change their basic premise(Eli Lilly
2000b). The message to the sales reps was still the
same in a September 2001 hyperglycaemia/diabetes
resource guide:
Market research has shown that ALL of our
competitors are talking about a supposed link
between hyperglycemia/diabetes and ZYPREXA.
This is one of the biggest issues we face in the
marketplace. The exciting thing is that we have
more data than ever to back up our story of
comparable rates of hyperglycemia and diabetes
across psychotropic agents.It is critical to our
success that we share this information with
physicians (Eli Lilly 2001b).
Internal documents addressed to sales reps mostly
refer to physicians, pharmacists and other health
professionals as customers. The September 2001
resource guide went on to note: For tough customers,
the use of the Hyperglycemia Sell Sheet followed by the
Study Comparison Insert increased the believability
of the comparable ratesmessageand concluded:
Customers require lots of repetition for message
recall and true behaviour change. Slides from
2001,tobeusedinsalesreptrainingreflectedthat
minimizing discussion of hyperglycaemia/diabetes
where possible was company sales strategy (Eli
Lilly 2001b;seeFigs.6and 7).
Fig. 7 Excerpt from olanzapine sales representative training
material
Bioethical Inquiry
A series of emails in March and April 2002
reveal that Eli Lilly was extremely keen to avoid
regulatory product information label changes to
not use Zyprexa in patients with diabetes or a
history of diabetesand contain a warning
statement that some patients may experience a
marked increase in blood glucose during Zyprexa
administrationas proposed by Japanese regulators
(Cavazzoni 2002a,b;Kerr2002). A verbatim
statement was drafted on the issue that Lillys
fundamental position regarding incidence of hyper-
glycemia and/or diabetes across antipsychotic class
continues to be comparable rates’” and further that
Lilly stands by its science, and is exploring several
options to correct this regulatory injustice.Butthe
issue persisted and by November 2002 an email on
the Japanese label issue stated: What is the strategy
regarding diabetes? Are we trying to show through
retrospective studies that it isntthatbigofaproblem?I
understand that we are trying to neutralize the issue, but
how are we trying to do that?(Aubuchon 2002). On 15
September 2003 Eli Lilly received letter from FDA
requesting inclusion of warning regarding hyperglyce-
mia and diabetes in labelingfor the US market (Eli
Lilly undated-f).
By January 2004 the Eli Lilly Wei ght Task
Forcesuggested A major change in tone and
approach is required (empathic with conviction) to
restore confidence...weight gain will no longer be
handled as an objection. Instead weight gain will be
discussed up front, integrated into the brand
promise(Eli Lilly 2004). Nonetheless a December
2003 PowerPoint presentation for the sales reps
concerning managing weight gain and diabetes
concernssuggested a less empathic approach (Eli
Lilly 2003;seeFig.8).
Quetiapine: Managing Side Effects
In a somewhat similar manner, data regarding weight
gain on quetiapine were managed by AstraZeneca.
One internal document, titled Seroquel Speakers
Slide Kitfrom March 2001, was apparently utilized
to educate physicians regarding the safety and
efficacy of the drug (AstraZeneca 2001). One slide
makes the claim, in bold, that Long-term Seroquel
has neutral effect on weight,while another stated
Seroquelweight neutral at all doses. Several other
slides make similar claims. These slides were based
on studies examining the drug in the treatment of
schizophrenia. Another set of slides, included in a
2003 email, were said to represent a core detail
flowto support our current position for Seroquel in
the treatment of schizophrenia. One slide stated
that: Seroquel, unlike some other antipsychotics, is
not associated with meaningful weight gain
(AstraZeneca 2003).
Yet in July 2008, an internal analysis of quetiapine
studies in schizophrenia conducted from 1993 to 1999
concluded that the incidence rate in adult patients
with weight gain 7% in all trials was 18.2%and
that in placebo-controlled trials, the relative risk of
clinically significant weight gain was 2.5 (Alam and
Jeffries 2008). The document noted that the results
of the analysis show that long-term treatment with
quetiapine monotherapy was associated with moder-
ate weight gain in patients with schizophrenia.
However, a journal publication in 2000, with a lead
AstraZeneca author, concluded that based on data
from clinical trials with patients with schizophrenia,
quetiapine had a neutral effect on weight (Brecher et
al. 2000). A physician practicing EBM may have
examined this study and concluded that quetiapine
was weight-neutral when the internal data indicated
that weight gain was a common side effect of the
drug.
1
Despite marketing claims to the contrary, employees
at AstraZeneca were concerned about quetiapine-
induced weight gain as early as 1997. In one email,
written regarding an apparently fluke study associating
quetiapine with weight loss, an employee noted that we
Fig. 8 Excerpt from olanzapine sales rep training for managing
customer (physician) concerns regarding weight gain and
diabetes
1
One of the authors (PP) prescribed quetiapine to several
patients due to its promotion as weight-neutral (based on
publicly available EBM at the time) and was quite surprised
when some patients experienced significant weight gain.
Bioethical Inquiry
must not get too carried away with weight loss when we
know the rest of our data appears to point in the other
direction(Hough 1999). In another email, a company
physician who worked with quetiapine noted that trial
results consistently found that, over time, weight gain
doesnt stopthe slope just appears to change
(Arvanitis 1997). A brief synopsis of several relevant
documents on the topic of quetiapine and weight gain
is available online (Edwards 2009b).
Disease Mongering
Disease mongeringrefers to the practice of expanding
the recognised boundaries of a disease entity to
encompass subclinical, borderline and normal range
symptoms in order to increase prescriptions and sales for
a drug or therapy (Moynihan et al. 2002). Internal
industry documents concerning Eli Lillys atypical
antipsychotic olanzapine (Zyprexa) suggest the com-
pany saw the potential to increase sales not only by
gaining indication for the management of all phases of
bipolar disorder, but for utilizing marketing tactics that
expanded the boundaries of the illness itself.
Eli Lillys original lifeplandocument for olanza-
pine in 1994 described the marketing profile for
olanzapine as the safer clozapine; the market was to
be schizophrenia and there was no mention of bipolar
disorder (Eli Lilly 1994). However the companys
patent on its bestselling antidepressant fluoxetine
(Prozac) was due to expire in August 2001. Slides
from a PowerPoint presentation at a meeting of the
Zyprexa Product Team, 25 July 2001, stated The
company is betting the farm on Zyprexa. The ability
of Eli Lilly to remain independent and emerge as the
fastest growing pharma company of the decade
depends solely on our ability to achieve world class
commercialization of Zyprexa(Eli Lilly 2001c,
italics in original). Graphs and text in the Zyprexa
Product Team summaryfrom 1997 referring to
Global Zyprexa Bipolar Forecastindicated sales
projections for the year 2000 would increase more
than fourfold if Zyprexa could be viewed as a
Depakote-like...MOOD-STABILIZERrather than
aRisperdal-like...Antipsychotic(Tollefson 1997).
A slide titled Bipolar Vision of Product Evolution
stated: To be a leader in the bipolar market, Zyprexa
will need to be viewed as a true mood stabilizer.A
true mood stabilizer will work in acute manic
episodes without inducing depression, acute depres-
sion without inducing mania, and protect the patient
from future episodes of mania or depression. These
are noble aims but the same document indicated the
company did not yet have the data to support such a
goal.
An internal company PowerPoint presentation on
Zyprexa PCP [Primary Care Physician] Vision
stated that a goal was to Expand our market by
redefining how primary care physicians identify,
diagnose and treat complicated mood disorders (i.e.
Bipolar Disorder)(Eli Lilly 2002b). A slide featured
in Fig. 9shows that the move into primary care was
recognized as a challenge. Physicians in primary care
did not typically treat bipolar disorder and used
antipsychotic medications infrequently, partially due
to safety concerns. The company, however, aimed to
change their paradigm. Part of this marketing
campaign was to broaden the concept of bipolar
disorder to include complicated mood,comprised
of some combination of anxiety, disruptive sleep,
irritability, and mood swings (Spielmans 2009). This
new type of patient was a source of untapped growth
potentialfor the drug. Additionally, fictional patient
vignettes were created for sales reps that highlighted
possible bipolar disorder or complicated moodin
cases of relatively minor mood instability that did not
meet current diagnostic manual (DSM-IV, ICD-10)
criteria for bipolar disorder I diagnosis. These
vignettes were to be used in sales visits to help
physicians identify patients who might suffer from
complicated moodsymptoms. To handle objections
from physicians who indicated they did not treat
schizophrenia or bipolar disorder, a script read:
Fig. 9 Eli Lilly slide regarding perceptions of primary care
physicians toward bipolar disorder
Bioethical Inquiry
Doctor, would you agree that you see patients who
present with symptoms of mood, thought, and
behavioural disorders who are not responding to your
satisfaction(Eli Lilly undated-g). Thus, physicians
who worked with exceedingly few patients who met
diagnostic criteria for olanzapines indications were
encouraged to simply look for patients who had
symptoms as opposed to the full-blown disorder in
question.
These documents, with reference to changing and
expanding the diagnostic paradigm for bipolar disorder,
are of great topical interest in the context of the current
controversy over the boundaries of bipolar disorder
(Paris 2009). Despite valid concerns of late diagnosis
of bipolar disorder (Berk et al. 2006), there is evidence
of overdiagnosis of bipolar disorder in recent years in
adults (Goldberg et al. 2008; Zimmerman et al. 2008)
and children (Carlson 2009;HealyandLeNoury2007;
Moreno et al. 2007). It seems quite likely that
pharmaceutical marketing is related to the increasing
rate of bipolar diagnoses (Zimmerman et al. 2008;
Healy 2006; Healy and Le Noury 2007).
Market Segmentation
The lengthy Eli Lilly document titled Key Player
Playbookprovides insight into how marketing
messages are tailored specifically to certain charac-
teristics of a physician. Physicians were broken into
five segments: Rule Bound, High Flyer, Skeptical
Experimenters, Selective Majority, and Systematic
Conservatives (Eli Lilly undated-a).Atthetimethe
document was written, olanzapine marketing was
focusedonHighFlyersandRuleBounds.
High Flyers were described as physicians who
were defined by the statement I eagerly seek out new
ways to treat my patients (first to adopt new
medicines). These were the physicians on the cutting
edge of medicine. Other descriptions of this segment
of physicians were as follows:
&Not bound by rules, guidelines, or system...
&Treat based on symptoms, not formal diagnosis
&Will push the envelope with off-label doses and
indications...
Based on this profile, olanzapine marketers were
encouraged to utilize a few specific tactics to sell the
drug. It was noted that High Flyers like to receive
pharmaceutical company sponsored programs and
tools in funenvironments. They were also noted as
being highly responsive to discussions with sales
reps, likely because High Flyers viewed reps as
providing the source of latest information. It was
also noted that they might like to become part of a
forum/club, presumably formed by the company, to
reinforce NS [neuroscience] leadership in a social
way. A skeptic might note that this technique could
be taking advantage of a certain vanity believed to
exist in the High Flyers, who would appreciate their
leadershipbeing recognized by a drug company.
To sell the exact same drug to a different group, the
Rule Bounds,a much different approach was
recommended. While the High Flyers did not play
by the rules, Rule Bounds were described as follows:
&I follow the rules when treating my patients; if
you dont follow the rules, youll pay for it later
&Diagnosis clearly determined for treatment
&Wait to use medication when well established in
the system
Rule Bounds were to be reassured that they were
following treatment guidelines. It was advised that
Rule Bounds should be placed with physicians who
could discuss what everyone is doing.Itseems
likely that the other physicians would be carefully
selected by Lilly to make sure to describe olanzapine as
the drug that everyoneis prescribing, thus catering to
the tendency of Rule Bound physicians to use well-
establishedmedications. Another document cited the
companyssuperior recruiting capabilities so the right
doctors go to the right programs,then referencing both
sales rep visits and peer-to-peermarketing, where
physicians would market the drug to their peers (Eli
Lilly 2002c).
The other types of physicians (Skeptical Experi-
menters, Selective Majority, and Systematic Conser-
vatives) were perceived as less likely to respond to
marketing than Rule Bounds and High Flyers. Thus,
marketing resources were targeted toward the most
easily influenced physicians, enabling Eli Lilly to
achieve a greater return on its marketing investment.
Potential Remedies
MBM likely leads to poorer outcomes and increased
costs. The time is ripe to reform how data from
Bioethical Inquiry
pharmaceutical trials are disseminated. Clearly, better
access to raw data is needed. Clinical trial registries
have not solved the problem; even among trials which
appear in such registries, selective reporting of
outcomes is common (Mathieu et al. 2009). Editors,
peer reviewers, and readers of trial results should
check online registry entries to verify whether the
data in a published clinical trial match the results and
protocol in the registry. In addition, public access to
regulatory agency reports would also be useful, as
there is often a notable discrepancy between data
received by regulatory agencies and data published in
medical journals (e.g., Turner et al. 2008a). Public
access to both trial protocols and results would greatly
increase transparency and allow physicians and
consumers to better assess the validity of clinical trial
results (Chan 2008).
More radical methods have also been proposed.
AformereditorofBMJ, Richard Smith, suggests
that journals should cease the publication of clinical
trials. Rather, trial protocols and results could be
published in some form of online registry. Journal
articles would then discuss the validity of these
trials. This may seem like an odd solution, but
there is in fact little evidence that peer review is
linked with notably better reporting of trial results
(Jefferson et al. 2007). Reprints of trials with
ostensibly positive results are often disseminated to
prescribers, a marketing strategy that one large
biomedical journal publisher calls invaluable for
direct marketing, exhibitions/seminars, sales cam-
paigns, and for mailing new product information to
physicians(Elsevier 2007). Further, reprints generate
revenue for journals; thus, Smith claims that editors may
feel pressured to publish trials that could make profits
for the journals publisher regardless of the trialsquality
(Smith 2005). Indeed, Smith estimated that one
especially profitable reprint used to market the now
disgraced painkiller rofecoxib generated about
$450,000 for the publisher (Smith 2006). Such
conflicts of interest could be eliminated if journals no
longer published clinical trials. However, it seems
unlikely that publishers would want to reduce their
profitability by simply giving up publication of clinical
trials. These reforms may seem drastic, but if we are
truly interested in providing the most safe and effective
treatments to patients, then the actual scientific
evidence regarding treatments must be made publicly
available.
Conclusion
Internal industry documents allow a glimpse into the
shadowy world of MBM, where data serve the needs of
marketing and inconvenient data are often recast as
positive or buried entirely. If, on the other hand, we are to
fulfil the worthy ambitions of EBM, all data collected in
clinical trials would be easily accessible. Journal articles
would accurately represent the underlying data and
individual contributors to a study would be given credit
for their role in conducting research. Marketing efforts
would contain accurate information. However, in the
current world of MBM, journal articles are an overly
positive representation of safety and efficacy, articles are
often prepared by drug marketers (whose influence is
hidden by honorary authors), marketing efforts contain
misleading information about both diseases and treat-
ments, and physicians are partitioned into market seg-
ments in order to best persuade them to believe various
marketing pitches. Until such issues are resolved,
particularly those regarding widespread access to accu-
rate data, any great enthusiasm for so-called evidence-
based medicine should be viewed with scepticism.
Limitations
The industry argues in court that subpoenaed documents
are taken out of context. This should be considered by
readers of the above excerpts. A fuller picture is available
from reading the many documents released and posted
on the internet (e.g., http://www.furiousseasons.com/
zyprexadocs.html,http://www.furiousseasons.com/
zip/seroqueldocs.zip,www.healthyskepticism.org/
documents/Antipsychotics.php). However, having read
through hundreds of such documents the authors found
little to contradict and much to support the conclusions
proffered here.
Acknowledgements The authors wish to acknowledge the
work of journalist, Philip Dawdy, who has written much on
these documents and whose website www.furiousseasons.com
is one of the main hosts of internal industry documents. We also
recognize the work of journalist Jim Edwards (http://industry.
bnet.com/pharma/blog), who has written much about several of
the documents discussed in this paper.
Disclosures Glen I. Spielmans has holdings of less than
$10,000 in a mutual fund (Vanguard Health Care), which
invests nearly exclusively in pharmaceutical companies. Dr.
Parry is a member of Healthy Skepticism.
Bioethical Inquiry
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Bioethical Inquiry
... 36 37 40 In addition, referencing past research using pharmaceutical industry documents, the documents were assessed for references to marketing to consumers such as unbranded campaigns. [52][53][54] The industry's targeted marketing to groups that had been disproportionately affected by the opioid epidemic was independently identified by all authors as a unique category for coding. When multiple documents made similar claims or presented similar ideas they were categorised together. ...
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... 20 Second, the people's trust over the vaccine will take time, and finally, the challenge against the misinformation by antivaccination campaigners. 21 The major limitation of the study was the short duration, so as to know the public's initial attitude toward COVID-19 vaccine. After the survey was finished and at the time of submission of the manuscript, we found an increased awareness among the public and more people were accepting the COVID-19 vaccine. ...
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... Drug promotional communications, such as sales aids, have been found to contain selectively extracted preliminary and exploratory data from clinical studies that, when taken out of context, may exaggerate the drug's benefits [2]. Furthermore, internal documents from the pharmaceutical industry illustrate that omission and spin of negative data are not uncommon in marketing materials [3], and a review of warning letters issued by the U.S. Food and Drug Administration (FDA) found that brochures and sales aids accounted for the largest proportion of regulatory violations [4]. ...
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... The prescription decision should be based on scientific evidences to avoid side effects and improve patients' treatment outcomes. However, the current studies are not reliable because they either withhold the negative outcomes of trials or suppressed it to use in the best interests of products and company (Spielmans & Parry, 2010). Furthermore, they use obsolete data or references from spurious journals. ...
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... It is noteworthy that rational prescription is based on scientific shreds of evidence and the advised medicines are best suited for them. However, in scientific trials, the negative effects are concealed and spanned, to best serve the commercial objective of the organisation (Spielmans & Parry, 2010). Some physicians observed that the references used are outdated and obsolete. ...
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Chapter
Internationally, efforts promoting greater transparency and improved management strategies for conflicts of interest (COI) have gained traction in healthcare settings. This particularly pertains to the development and use of clinical practice guidelines (CPG). Mounting evidence indicates that pharmaceutical industry payments to GPG authors and developers influence clinical recommendations, including drug selection, often to benefit commercial interests and at the expense of patients. To prevent undue influence of COI and develop trustworthy CPG, authors and developing organizations should establish strict COI management policies, including full disclosure. Such policies should include details about the monetary values and funding sources of all payments and gifts from pharmaceutical companies. Authors and developers should refuse any payments or gifts while drafting CPG. CPG developers should establish clear and comprehensive COI definitions and create monitoring committees that implement COI policies, promote external review, and track COI declared by CPG authors using existing payment databases.
Chapter
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In this paper, we address the question of ‘Why do firms publish scientific papers?’. Research examining the competitive advantages that firms accrue from investment in R&D has provided evidence that such efforts can be associated with the voluntary disclosure of research findings in scientific publications. This form of scientific openness occurs despite potentially undermining the value-capturing process by generating knowledge spillovers and hindering the use of other instruments for protecting intellectual property (patents and secrecy). Our understanding of what leads firms to engage in scientific publishing remains relatively limited, however. We address this gap by presenting a systematic review of 164 studies examining firm publishing. We then develop a conceptual framework that outlines five incentives for firms to engage in publishing: (i) accessing external knowledge and resources; (ii) attracting and retaining researchers; (iii) supporting IP strategies; (iv) building the firm's reputation; and (v) supporting commercialization strategies. Mechanisms that relate incentives to publish to firms' major stakeholders – i.e. academia, industry, investors, users, and institutions – are also outlined in the framework. We conclude by setting out an agenda for future research.
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Background Industry relationships and conflicts of interest can impact research funding, topics, and outcomes. Little research regarding the role of biomedical companies at microsurgery conferences is available. This study evaluates the role of industry at conferences by comparing payments received by speakers at the American Society for Reconstructive Microsurgeons (ASRM) meeting with those received by speakers at the American Society of Aesthetic Plastic Surgeons (ASAPS) meeting, the American Society of Plastic Surgeons (ASPS) meeting, and an average plastic surgeon. It also compares payments made by different companies. Methods General payments received by speakers at the 2017 ASAPS, ASPS, and ASRM conferences were collected from the Open Payments Database. Mean payments received at each conference were calculated and the Mann–Whitney U test evaluated differences between conference speakers and the average plastic surgeon. The total amount of payments from each company was collected through the Open Payments Database, and Z-tests identified which companies paid significantly more than others. Results The mean (and median) general payments made to conference speakers at ASAPS (n = 75), ASPS (n = 247), and ASRM (n = 121) were $75,577 ($861), $27,562 ($1,021), and $16,725 ($652), respectively. These payments were significantly greater (p < 0.001 for all) than those of the average plastic surgeon ($4,441 and $327), but not significantly different from each other. Allergan contributed significantly more than other companies to speakers at ASPS and ASAPS, while LifeCell Corporation, Zimmer Biomet Holdings, and Axogen contributed significantly more to speakers at ASRM. Conclusion Payments to physicians at ASRM were significantly higher than those of an average plastic surgeon but not significantly different from those of speakers at ASAPS and ASPS. Certain companies paid significantly more than their peers at each conference. Given these findings, speakers should strive to make clear the nature and extent of their conflicts of interest when presenting at conferences.
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This article casts a critical eye over the development of American psychiatry from 1980 to the present. It notes the rapid decline of psychoanalysis that followed the publication of DSM III; the rising influence of genetics and neuroscience; the re-emphasis on the biology of mental illness; and the collapse of public psychiatry that accompanied deinstitutionalization. It argues that while genetics and neuroscience have made scientific progress, the clinical utility of their findings to date has been very limited. The fifth edition of the DSM was supposed to base itself on this new science but that proved impossible. Diagnosis remains purely phenomenological and controversial. One of the ironies of research on psychiatric genetics is that has failed to find either a Mendelian origin of schizophrenia and depression or to validate the importance of hypothesized candidate genes. Genome-wide association studies have instead uncovered risk factors for major mental illnesses, but these overlap considerably, and the genetic associations are not dispositive. Most of those who carry these genetic variants do not develop mental illness. The status of psychopharmacology since the mid-1950s is scrutinized, as is the influence of the pharmaceutical industry on contemporary psychiatry, and the implications of its recent decision to abandon work in this arena. The paper concludes with an assessment of the crisis that it contends confronts contemporary American psychiatry: its overemphasis on biology; the urgent questions that persist about diagnosis and therapeutics; concerns about the directions of future research; and its inability to reduce the excess mortality that plagues the mentally ill.
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In the past decade bipolar disorder in children has been diagnosed with rapidly increasing frequency in North America, despite a century of psychiatric consensus that manic-depressive illness rarely had its onset before adolescence. This emergence has happened against a background of vigorous pharmaceutical company marketing of bipolar disorder in adults. In the absence of a license demonstrating efficacy for their compound for bipolar disorder in children, however, companies cannot actively market pediatric bipolar disorder. This paper explores some mechanisms that play a part in spreading the recognition of a disorder in populations for which pharmaceutical companies do not have a license. These include the role of academic experts, parent pressure groups, measurement technologies and the availability of possible remedies even if not licensed.
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A lot of money can be made from healthy people who believe they are sick. Pharmaceutical companies sponsor diseases and promote them to prescribers and consumers. Ray Moynihan, Iona Heath, and David Henry give examples of “disease mongering” and suggest how to prevent the growth of this practiceThere's a lot of money to be made from telling healthy people they're sick. Some forms of medicalising ordinary life may now be better described as disease mongering: widening the boundaries of treatable illness in order to expand markets for those who sell and deliver treatments. 1 2 Pharmaceutical companies are actively involved in sponsoring the definition of diseases and promoting them to both prescribers and consumers. The social construction of illness is being replaced by the corporate construction of disease.Whereas some aspects of medicalisation are the subject of ongoing debate, the mechanics of corporate backed disease mongering, and its impact on public consciousness, medical practice, human health, and national budgets, have attracted limited critical scrutiny.Within many disease categories informal alliances have emerged, comprising drug company staff, doctors, and consumer groups. Ostensibly engaged in raising public awareness about underdiagnosed and undertreated problems, these alliances tend to promote a view of their particular condition as widespread, serious, and treatable. Because these “disease awareness” campaigns are commonly linked to companies' marketing strategies, they operate to expand markets for new pharmaceutical products. Alternative approaches—emphasising the self limiting or relatively benign natural history of a problem, or the importance of personal coping strategies—are played down or ignored. As the late medical writer Lynn Payer observed, disease mongers “gnaw away at our self-confidence.”2Although some sponsored professionals or consumers may act independently and all concerned may have honourable motives, in many cases the formula is the same: groups and/or campaigns are orchestrated, funded, and …
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Selective reporting is prevalent in the medical literature, particularly in industry-sponsored research. In this paper, we expose selective reporting that is not evident without access to internal company documents. The published report of study 329 of paroxetine in adolescents sponsored by GlaxoSmithKline claims that "paroxetine is generally well tolerated and effective for major depression in adolescents". By contrast, documents obtained during litigation reveal that study 329 was negative for efficacy on all 8 protocol specified outcomes and positive for harm.
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As of 2005, the International Committee of Medical Journal Editors required investigators to register their trials prior to participant enrollment as a precondition for publishing the trial's findings in member journals. To assess the proportion of registered trials with results recently published in journals with high impact factors; to compare the primary outcomes specified in trial registries with those reported in the published articles; and to determine whether primary outcome reporting bias favored significant outcomes. MEDLINE via PubMed was searched for reports of randomized controlled trials (RCTs) in 3 medical areas (cardiology, rheumatology, and gastroenterology) indexed in 2008 in the 10 general medical journals and specialty journals with the highest impact factors. For each included article, we obtained the trial registration information using a standardized data extraction form. Of the 323 included trials, 147 (45.5%) were adequately registered (ie, registered before the end of the trial, with the primary outcome clearly specified). Trial registration was lacking for 89 published reports (27.6%), 45 trials (13.9%) were registered after the completion of the study, 39 (12%) were registered with no or an unclear description of the primary outcome, and 3 (0.9%) were registered after the completion of the study and had an unclear description of the primary outcome. Among articles with trials adequately registered, 31% (46 of 147) showed some evidence of discrepancies between the outcomes registered and the outcomes published. The influence of these discrepancies could be assessed in only half of them and in these statistically significant results were favored in 82.6% (19 of 23). Comparison of the primary outcomes of RCTs registered with their subsequent publication indicated that selective outcome reporting is prevalent.
Article
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Recent suggestions to extend the boundaries of bipolar disorder to a broader spectrum lead to a concept of bipolarity different from that of classical psychiatry. It has been proposed that many patients with unipolar depression are actually bipolar and that many cases of substance abuse, personality disorders, and childhood behavioral disorders lie within the spectrum. However, since this expanded notion of bipolarity has been defined entirely on the basis of phenomenology, any expansion needs to meet broader criteria for validity. Bipolar spectrum disorders have a different phenomenology, family history, and course than classical bipolar disorders and do not respond in the same way to drugs. Until further research clarifies the boundaries of bipolarity, we should be conservative about extending its scope.
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Background: Internal documents from the pharmaceutical industry provide a unique window for understanding the structure and methods of pharmaceutical promotion. Such documents have become available through litigation concerning the promotion of gabapentin (Neurontin, Pfizer, Inc., New York, New York) for off-label uses. Purpose: To describe how gabapentin was promoted, focusing on the use of medical education, research, and publication. Data Sources: Court documents available to the public from United States ex. rel David Franklin vs. Pfizer, Inc., and Parke-Davis, Division of Warner-Lambert Company, mostly from 1994-1998. Data Extraction: All documents were reviewed by 1 author, with selected review by coauthors. Marketing strategies and tactics were identified by using an iterative process of review, discussion, and re-review of selected documents. Data Synthesis: The promotion of gabapentin was a comprehensive and multifaceted process. Advisory boards, consultants meetings, and accredited continuing medical education events organized by third-party vendors were used to deliver promotional messages. These tactics were augmented by the recruitment of local champions and engagement of thought leaders, who could be used to communicate favorable messages about gabapentin to their physician colleagues. Research and scholarship were also used for marketing by encouraging "key customers" to participate in research, using a large study to advance promotional themes and build market share, paying medical communication companies to develop and publish articles about gabapentin for the medical literature, and planning to suppress unfavorable study results. Limitations: Most available documents were submitted by the plaintiff and may not represent a complete picture of marketing practices. Conclusion: Activities traditionally considered independent of promotional intent, including continuing medical education and research, were extensively used to promote gabapentin. New strategies are needed to ensure a clear separation between scientific and commercial activity.
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Introduction: Quetiapine (Seroquel TM ) is an atypical antipsychoticdrug with demonstrated efficacy and tolerability. In particular, placebo-level extrapyramidal symptoms (EPS) across the entire dose range and a low propensity to cause sexual dysfunction suggest it may be associated with greater patient acceptability than alternative treatments. However, other side-effects, such as weight gain, may also have a significant impact on treatment acceptability. Method: We report the long-term weight changes observed in a cohort of 427 patients with schizophrenia from controlled and open-label extension (OLE) trials, in which quetiapine (mean dose 475 mg/day after 1 year) was the only antipsychotic medication during the OLE period. Results: In these patients, there was no overall effect on weight across the body mass index (BMI) spectrum. There were no dose-related effects on weight, and only one patient withdrew from treatment due to an adverse event of weight gain. Quetiapine appeared to have a weightneutral or 'normalizing' effect, with a tendency towards favourable shifts in bodyweight in underweight patients (BMI<18.5 kg/m 2 ) and severely obese patients (BMI>35 kg/m 2 ). Conclusion: These results indicate that long-term weight changes with quetiapine monotherapy are minimal and potentially beneficial, and do not appear to raise the medical concerns associated with some other atypical agents.
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Media reports have discussed how olanzapine was marketed off-label for dementia and subsyndromal bipolar disorder. Much of this marketing occurred in primary care settings. However, these reports have provided few details. In legal proceedings, Lilly disclosed internal documents that detail the strategies utilized to market olanzapine. The current paper addresses the marketing of olanzapine in detail based upon a review of these documents. All 358 documents released by Lilly are publicly available online. Documents were utilized for this review if they were relevant to the marketing of olanzapine in primary care settings in the United States. It was found that olanzapine was marketed off-label in primary care settings for relatively mild symptoms that were framed as bipolar disorder and schizophrenia. A key strategy in this campaign was the use of hypothetical patient profiles in detailing visits, most of which clearly failed to meet diagnostic criteria for any recognized mental disorder. Evidence emerged that olanzapine was also marketed off-label as a treatment for dementia.