Article

Under the Influence: The Interplay among Industry, Publishing, and Drug Regulation

Abstract and Figures

The relationships among academe, publishing, and industry can facilitate commercial bias in how drug efficacy and safety data are obtained, interpreted, and presented to regulatory bodies and prescribers. Through a critique of published and unpublished trials submitted to the Federal Drug Administration (FDA) and the European Medicines Agency (EMA) for approval of a new antidepressant, vortioxetine, we present a case study of the "ghost management" of the information delivery process. We argue that currently accepted practices undermine regulatory safeguards aimed at protecting the public from unsafe or ineffective medicines. The economies of influence that may intentionally and unintentionally produce evidence-biased-rather than evidence-based-medicine are identified. This is not a simple story of author financial conflicts of interest, but rather a complex tale of "ghost management" of the entire process of bringing a drug to market. This case study shows how weak regulatory policies allow for design choices and reporting strategies that can make marginal products look novel, more effective, and safer than they are, and how the selective and imbalanced reporting of clinical trial data in medical journals results in the marketing of expensive "me-too" drugs with questionable risk/benefit profiles. We offer solutions for neutralizing these economies of influence.
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Under the Influence: The Interplay among
Industry, Publishing, and Drug Regulation
Lisa Cosgrove Ph.D., Steven Vannoy Ph.D., Barbara Mintzes Ph.D. & Allen F.
Shaughnessy Pharm.D., M.Med.Ed.
To cite this article: Lisa Cosgrove Ph.D., Steven Vannoy Ph.D., Barbara Mintzes Ph.D. & Allen
F. Shaughnessy Pharm.D., M.Med.Ed. (2016) Under the Influence: The Interplay among
Industry, Publishing, and Drug Regulation, Accountability in Research, 23:5, 257-279, DOI:
10.1080/08989621.2016.1153971
To link to this article: http://dx.doi.org/10.1080/08989621.2016.1153971
Accepted author version posted online: 18
Feb 2016.
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Under the Influence: The Interplay among Industry,
Publishing, and Drug Regulation
Lisa Cosgrove, Ph.D.
a
, Steven Vannoy, Ph.D.
a
, Barbara Mintzes, Ph.D.
b
,
and Allen F. Shaughnessy, Pharm.D., M.Med.Ed.
c
a
Department of Counseling and School Psychology, University of Massachusetts Boston, Boston, MA,
USA;
b
Faculty of Pharmacy and Charles Perkins Centre, University of Sydney, Sydney, Australia;
c
Department of Family Medicine, Tufts University School of Medicine, Boston, MA, USA
ABSTRACT
The relationships among academe, publishing, and industry
can facilitate commercial bias in how drug efficacy and safety
data are obtained, interpreted, and presented to regulatory
bodies and prescribers. Through a critique of published and
unpublished trials submitted to the Food and Drug
Administration (FDA) and the European Medicines Agency
(EMA) for approval of a new antidepressant, vortioxetine, we
present a case study of the ghost management of the infor-
mation delivery process. We argue that currently accepted
practices undermine regulatory safeguards aimed at protecting
the public from unsafe or ineffective medicines. The economies
of influence that may intentionally and unintentionally pro-
duce evidence-biasedrather than evidence-basedmedicine
are identified. This is not a simple story of author financial
conflicts of interest, but rather a complex tale of ghost man-
agement of the entire process of bringing a drug to market.
This case study shows how weak regulatory policies allow for
design choices and reporting strategies that can make mar-
ginal products look novel, more effective, and safer than they
are, and how the selective and imbalanced reporting of clinical
trial data in medical journals results in the marketing of expen-
sive me-too drugs with questionable risk/benefit profiles. We
offer solutions for neutralizing these economies of influence.
KEYWORDS
Antidepressants; clinical
trials; conflict of interest;
ghostwriting; medical
journals; regulatory process
Introduction
There has been widespread discussion in the medical literature about the
influence
of sponsors on clinical trials of newly developed and marketed
medicines, resulting in calls for improved transparency and management of
conflicts of interest (Kesselheim et al., 2012). This is because industry-
sponsored trials are more likely to report positive results than independent
studies (Lundh et al., 2012) and researchers with financial ties to manufac-
turers are more likely to express industry favorable opinions (see, e.g.,
CONTACT Lisa Cosgrove Lisa.Cosgrove@umb.edu Department of Counseling and School Psychology,
University of Massachusetts Boston, 100 Morrissey Blvd., Boston, MA 02125, USA.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/GACR.
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Krimsky, 2003; Cosgrove et al., 2014). Millions of dollars in revenue can be
lost if there are delays in getting drugs approved, thus incentivizing sponsors
to influence research [design and dissemination] to advance their interests
(Tereskerz et al., 2009, p. 79). Therefore, it is not surprising that the pub-
lication of industry-sponsored research is governed by “‘publication plans ...
and always by carefully constructing papers that establish consistent profiles for
drugs (Sismondo, 2009, p. 172, emphasis added). As Elliott (2008) has noted,
it has become standard practice for pharmaceutical companies to pay medical
communication companies to write articles (based on industry-designed
studies), for academic physicians to be paid to essentially sign off on the
articles, and then for communication companies to place the articles in
prestigious medical journals, a process known as ghost management (see,
e.g., Ducet and Sismondo, 2008; Fugh-Berman, 2010; Healy and Cattell, 2003;
Jureidini and McHenry, 2011; Lacasse and Leo, 2010; McHenry and
Jureidini, 2008).
Ghost management has resulted in the selective and imbalanced reporting
of clinical trial data in medical journals, which in turn has supported the
marketing of expensive new drugs with questionable risk/benefit profiles
(Heres et al., 2006). Antidepressants have been especially subject to scrutiny.
Researchers have identified selective reporting of research findings that
exaggerates efficacy (Heres et al., 2006; Turner et al., 2008) and fails to report
the lack of benefit and harm done to children and adolescents (Garland,
2004). For example, an independent reanalysis of a study of paroxetine use in
adolescents (study 329) highlighted the observed increased risk of suicidality
and lack of efficacy, neither of which were reported in the original publica-
tion (Le Noury et al., 2015 ). Disclosure and management of financial conflict
of interests are insufficient strategies for protecting the integrity of science
because of the subtle but powerful ways that trial design and interpretations
of data can be influenced by commercial ties (Elliot, 2008).
Thus, there is clear evidence that the funding effect is real (Krimsky,
2013), and that it is important to take financial relationships into account
when assessing the integrity of research (Resnik and Elliott, 2013). Because
commercial interests may explain why the clinical trial literature displays
bias but not how that bias occurs (Doucet and Sismondo, 2008, p. 627), we
undertook a case study of a newly approved antidepressant, vortioxetine
(Brintellix). We identify the following three main problems that help
explain how bias occurs:
(1) Weak regulatory standards allow metoo drugs to be approved
without enough evidence of a clinically meaningful benefit that out-
weighs associated risks. That is, manufacturers only need to demon-
strate statistical significance over placebo; they are not required to
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demonstrate clinically significant efficacy over drugs currently on the
market.
(2) Clinical trials are not designed in the publics interest in terms of
obtaining adverse event data.
(3) Currently accepted publication practices, similar to regulatory ones,
do not require that researchers include comparisons of outcomes
between a new drug and comparator drugs. This omission can give
readers, often providers, the impression that the newly approved
drug is at least as efficacious, if not more so, than drugs already on
the market. Our analysis suggests t hat there is a c omplex interplay
among three institutions: the pharmaceutical industry, the medical
publishing industry, and the bodies that regulate medical com-
merce. The legal, accepted, and normative processes used by these
societal agencies, when brought together, result in a perturbation
that allows a product of questionable benefit to be marketed in
several countries. Our case study adds to the literature by addres-
sing the systemic issues, and economies of influence, that facilitate
publication planning and undermine the integrity of science. We
also offer suggestions on how small changes to reporting require-
ments and regulatory oversight can keep these institutions suffi-
ciently sepa rate so that the process regains its ability to protect
society fr om harm.
Exploring efficacy and tolerability
This case study is based on information available on the US Food and Drug
Administration
(FDA)s website, the European Medicines Agency (EMA)s
website, the trial registry clinicaltrials.gov, and published clinical trial reports.
To obtain reports of trials submitted for US approval and FDA analyses and
interpretation of trial results, we obtained FDA review reports for vortiox-
etine, which are posted online at http://www.accessdata.fda.gov/scripts/cder/
drugsatfda/index.cfm. We consulted the three FDA reports that discuss Phase
III clinical trial data: the Summary Review, the Medical Review, and the
Statistical Review, all available at http://www.accessdata.fda.gov/drugsatfda_
docs/nda/2013/204447Orig1s000TOC.cfm.
To obtain information on trials submitted for approval in Europe, and the
EMAs assessment of those trials, we obtained the European Public
Assessment Report (EPAR) for vortioxetine, which is posted on the EMAs
website, at http://www.ema.europa.eu/docs/en_GB/document_library/
EPAR_-_Public_assessment_report/human/002717/WC500159447.pdf.
We sought published reports corresponding to each of the trials listed in
the FDA review reports and the EMAs EPAR for vortioxetine. We first
searched the registry clinicaltrials.gov (search terms vortioxetine and
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intervention trials). Clinicaltrials.gov listings include the FDA identifier
and often also list publications, facilitating reconciliation. As not all clinical-
trial.gov entries reliably list published articles, we also searched Medline and
the reference lists of recent published systematic reviews for additional
publications (Meeker et al., 2015; Pae et al., 2015). Data for Table 2 (with-
drawals and withdrawals due to adverse events in active-controlled trials)
were obtained from the US FDA Medical Review report and published
articles. For Figure 2, we extracted data on mean differences in
Montgomery-Asberg Depression Rating Scale (MADRS) scores from baseline
for vortioxetine and active comparators from data provided in published
reports and in the EPAR, and used Review Manager 5.3 software for meta-
analysis, using fixed effects modeling. For information on trial sponsorship,
the sponsors role in the design, conduct, and publication of the trial, and
authors conflicts of interest, we relied entirely on published trial reports.
Limitations in the regulatory review process
Vortioxetine is a serotenergic antidepressant that was approved in the United
States
(US) and the European Union (EU) in late 2013. To establish vortiox-
etines efficacy in treating major depression, the manufacturers Lundbeck/
Takeda submitted 10 short term randomized controlled trials (RCTs) and
one longer term randomized drug withdrawal study to the FDA (Center for
Drug Evaluation and Research, 2012). The EMA reviewed these 11 trials and
two more recently published studies (European Medicines Agency, 2014)
(Table 1). One additional similar short-term RCT was not included in the
FDA or EMA report (Wang et al. 2015; Table 1).
Table 1. Overview of included clinical trials.
Published report
Clinicaltrials.
gov
FDA/
EMA N Duration
FDA
rating Active comparator?
Katona et al. (2012) NCT00811252 12541A 452 8 weeks positive duloxetine 60 mg
Mahableshwarkar et al.
(2013)
NCT00672620 304 611 8 weeks negative duloxetine 60 mg
Baldwin et al. (2012) NCT00635219 11984A 776 8 weeks negative duloxetine 60 mg
Boulenger et al. (2014) NCT01140906 13267A 608 8 weeks positive duloxetine 60 mg
Mahableshwarkar et al.
(2015a)
NCT01153009 315 614 8 weeks positive duloxetine 60 mg
Alvarez et al. (2012) NCT00839423 11492A 429 6 weeks positive venlafaxine XR 225 mg
Wang et al. (2015) NCT01571453 N/A 437 8 weeks N/A venlafaxine XR 150 mg
Jain et al. (2013) NCT00672958 303 600 6 weeks negative
Henigsberg et al. (2012) NCT00735709 305 560 8 weeks positive
Mahableshwarkar et al.
(2015b)
NCT01179516 317 469 8 weeks negative
Jacobsen et al. (2015) NCT01163266 316 462 8 weeks positive
Boulenger et al. (2012) NCT00596817 11985A 396 24 weeks N/A
McIntyre et al. (2014) NCT01422213 14122A 602 8 weeks N/A
Unpublished NCT01255787 CCT-002 600 8 weeks N/A
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The FDA concluded that six of the 10 short-term RCTs found vortioxetine
to be efficacious on at least one primary outcome measure, either the
MADRS) or Hamilton Depression Rating Scale (HAM-D), and four were
negative trials in which vortioxetine was no better than placebo in treating
depression symptoms. The FDA based its efficacy assessment on the subset of
trials judged to be positive. Within this subset, the FDA required at least one
positive result in order to consider vortioxetine efficacious (Center for Drug
Evaluation and Research, 2012).
Although this approach is a currently accepted practice by regulatory
agencies, it is in stark contrast to current systematic review and meta-analysis
standards (Figure 1), which assess treatment outcomes based on the full body
Literature search to gather all
relevant published and
unpublished research
Explicit inclusion criteria:
study design,
participants,
intervention, comparator
Exclude
articles not
meeting
inclusion
criteria
Full set of included studies
identified (n= xx )
Meta-analyses of all relevant
data per outcome, to obtain
summary estimates of
treatment effects
Data extraction, appraisal
for risk of bias, authors
contacted for missing data
Manufacturer carries out pre-
market clinical trials
All clinical trials listed in
regulatory review;
classified as phase I, II, III;
pivotal or non pivotal
FDA carries out detailed
efficacy analysis on a
subset (pivotal trials) and
those with positive results
Trials with
negative
results only
evaluated for
harm, not
effectiveness
Interpretation of benefit
and harm is based on all
available trials, taking
study quality and risks of
bias into account.
Interpretation of benefit is
based on the subset of
positive trials only. Harm
assessment is based on
the full data set.
Systematic review
approach – gather all
the evidence
FDA approach – focus
on the positive
Figure 1. Comparison of the approaches used by systematic reviews and the FDA to determine
drug efficacy.
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of available clinical trial evidence (Higgins and Green, 2011). Because there is
chance variation in trial outcomes, a focus only on a selected subset of
positive results will inaccurately inflate treatment effects. If treatment effects
are marginal, the balance can be tipped from a judgment of non-efficacious
to efficacious.
Similarly to the FDA, the EMA judged that, the efficacy of vortioxetine
was demonstrated with at least one dosage group across 9 of the 12 studies
(European Medicines Agency, 2014). This was based on at least a 2-point
greater change from baseline than placebo on the 60-point MADRS scale.
The FDA also defined primary efficacy as the change from baseline to
endpoint of either MADRS or HAM-D24 total score (Center for Drug
Evaluation and Research, 2012). Neither the FDA nor the EMA required
efficacy to be established in terms of a clinically relevant outcome, such as the
proportion of patients achieving remission or other functional outcomes
such as return to work.
Additionally, neither agency focused on direct comparisons between vor-
tioxetine and another antidepressant, although six of the trials included
direct comparisons. From a clinical care perspective, whether a new treat-
ment is better or worse than existing options is very important. We carried
out a meta-analysis of results of the six studies that used an active compara-
tor (duloxetine or venlafaxine), plus a seventh more recent trial versus
venlafaxine not included in the FDA and EMA reviews (Figure 2). Overall,
the comparator was significantly more effective than vortioxetine at three of
the four dose levels tested, including the highest dose, 20 mg, with mean
Figure 2. Exploring efficacy: Differences in mean change from baseline in MADRS score between
vortioxetine and active comparators (duloxetine 60mg, venlafaxine 225mg or venlafaxine XR
150mg).
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differences ranging from 1.7 points (95% CI 0.5 to 2.8) at 5 mg to 3.4 points
(95% CI 1.8 to 5.0) at 15 mg. Only at the 10 mg dose level were effects
similar: 0.2 points (95% CI 1.5 to 1.1). Only one published report (Wang
et al., 2015) directly reports the comparison between vortioxetine and an
active comparator, venlafaxine XR 150 mg. This trial lists a criterion of <2.5
points for the upper confidence interval as the a priori criterion for non-
inferiority. Of the 11 dose-specific comparisons listed in Figure 2, vortiox-
etine only met the non-inferiority criterion in this one case. The rest of the
published articles only report comparisons between vortioxetine and placebo,
and the active comparator and placebo, although data in these articles and
the EMA report (European Medicines Agency, 2014) allows for these
comparisons.
Some readers might ask, How could the FDA and EMA approve a new
drug that appears to be less effective than other available antidepressants, and
which failed to be more effective than placebo in a substantial subset of
trials? The short answer is that regulatory standards for efficacy are not as
strong as prescribers or the public may think: efficacy is defined in terms of a
chosen effect, which may or may not be clinically relevant (Bero and
Rennie, 1996).
A contrast between researchers and
regulators assessments
Authors of a recent independent (i.e., non-industry funded or affiliated)
meta-analysis
of the same short term RCTs that the FDA and EMA reviewed
reached the conclusion, Vortioxetine does not appear to be more effective,
and is potentially less effective, than an SNRI [serotonin and norepinephrine
reuptake inhibitor] (Meeker et al., 2015). Another independent systematic
review explicitly addressed the difference between statistical and clinical
significance: It is questionable whether the overall SMD [standardized
mean difference] of 0.22 between vortioxetine and placebo groups is suffi-
ciently large to translate into clinical significance (Pae et al., 2015). This
effect size corresponds to approximately a 2 point difference on the MADRS
scale. They further conclude: the efficacy of vortioxetine may meet the
marginal standard criterion for an antidepressant to be considered effective
for treating MDD [Major Depressive Disorder] and although our results
suggest that vortioxetine may be an effective treatment option for MDD, they
should be interpreted and translated into clinical practice with caution (Pae
et al., 2015, emphasis added).
Selective outcome reporting and gaming the risk/benefit profile
The published studies do not give readers this message of marginal
effectiveness.
They feature abstracts and conclusions that frequently
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overstate benefit, using broad phrases such as efficacious and well-
tolerated (Alvarez et al., 2012;Boulenger,Loft,andOlsen,2014;
Katona, Hansen, and O lsen, 2012) without further explanations of the
small magnitude of effect, limits of the study designs, patient selection,
and limited trial duration ( Figure 3). Indeed, given the extensive doc-
umentation of the problematic adverse event (AE) profile of serotonergic
agents, a trial design in the publics interest should include active
collection of AE data and tolerability, including assessment of withdra-
wal effects. Because the AE profile of serotonergic drugs is now well
understood, only when there is active collection of AE data and
robust results should researchers conclude that vortioxetine is well-
tolerated.
Examination of the data on early withdrawals due to adverse events and
total withdrawals in active-comparator trials raises questions about claims of
a tolerability advantage for vortioxetine (Table 2). According to the published
The strategy to adjust for multiple comparisons was inconsistent with
guidelines for that procedure, likely increasing the false positive rate. (100%) *
Unadjusted p-values were reported for comparisons that should not
have been conducted according to stated methods. These unadjusted
p-values provide a false impression that results were statistically
significant when they were not. (82%)*
Reporting of results over-emphasized marginal statistical significance and
ignored the small effect sizes indicating a failure to reach clinical significance.
(75%) *
The majority of study participants were severely depressed, favoring a positive
outcome, but this feature is not obvious in the reports. (100%) *
Mixed Effect Model Repeated Measure was commonly presented as a
comprehensive solution to missing data. However, in certain circumstances,
(e.g., when the subjects in the treatment arm drop out more quickly than those
in the placebo arm and drop-outs tend to have worse outcomes), this model is
inappropriate and can increase the false positive rate. No data were presented
on differences in dropout with respect to time. (92%) *
Analytic details are often inadequately reported. For example, no data were
presented with respect to study site differences or their impact on the
modeling. (92%)*
*percentage of studies demonstrating this problem
Figure 3. Design choices, methodological strategies, and inadequate reporting giving an inflated
impression of efficacy.
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trial results and the FDA and EMA reports, most of the AE data in trials were
obtained through spontaneous reports (Center for Drug Evaluation and
Research, 2012 ; European Medicines Agency, 2014). At clinical visits,
patients were asked a single question, how do you feel? This represents a
passive approach to AE ascertainment, as compared with actively questioning
patients about the presence or absence of specific events known to be
associated with this antidepressant class (Figure 4). Sexual dysfunction is
one of the most frequent side effects of serotonergic antidepressants, and
relying on spontaneous reporting of sexual difficulties is a good way to
ensure that the number of AEs related to sexual dysfunction is low. As
Loke and Mattishent (2015) note in a recent commentary on inadequate
adverse event reporting in clinical trials of antibiotics, if you dont look
properly, you wont find (see also Shamoo, 2001). For example, the relapse
study, which only used spontaneous reporting of all side effects, including
treatment emergent sexual dysfunction concluded, [vortioxetine] was well
tolerated as a maintenance treatment with low incidence of sexual side-
effects (Boulenger, Loft, and Florea, 2012). Highlighting tolerability may
also give the clinician the false impression that vortioxetine has a better side
effect profile than other serotonergic antidepressants.
Moreover, in the few trials that used a sexual dysfunction scale (the Arizona
Sexual Experiences [ASEX] scale), the vast majority of participants (between 2/3
to 3/4) met the criteria for sexual dysfunction at baseline, rendering the validity
of the instrument questionable, and making it impossible to draw any valid
conclusions about treatment emergent sexual side effects as dysfunction was
only assessed among the small minority judged to be ‘“normal at baseline. Yet,
Table 2. Tolerability: Early withdrawals due to adverse events and total withdrawals.
Vortioxetine Comparators
5mg 10mg 15mg 20mg Placebo
Duloxetine
60mg Venlafaxine XR*
Withdrawals due to adverse events (% per study arm) *
Katona et al. 2012 6.4 4.1 9.9
Mahableshwarkar et al. 2013 7.8 4.6 11.2
Baldwin et al. 2012 11.6 9.9 8.3 12.8
Boulenger et al. 2012 6.7 11.3 4.4 4.8
Mahableshwarkar et al. 2015a 9.5 9.1 2.5 6.6
Alvarez et al. 2012 2.8 6.5 3.8 14.3
Wang et al. 2015 6.6 14.2
Total withdrawals, all causes (% per study arm)
Katona et al. 2012 12.8 11.7 15.2
Mahableshwarkar et al. 2013 20.3 21.6 27.6
Baldwin et al. 2012 22.6 22.5 17.2 28.2
Mahableshwarkar et al. 2015a 23.1 26.6 19.9 24.3
Boulenger et al. 2012 22.5 17.2 15.8 10.9
Wang et al. 2015 17.8 27.0
Alvarez et al. 2012 9.3 18.0 17.1 17.9
*dose 225mg/day in Alvarez et al. 2012; 150mg/day in Wang et al. 2015.
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in the abstract of one of the published trials, the following finding was high-
lighted: ASEX total scores were similar across [placebo and treatment] groups
(Mahableshwarkar et al., 2015). This statement gives the reader the false impres-
sion not only that a conclusion about sexual side effects could be made, but also
that vortioxetine had a favorable side effect profile for treatment emergent sexual
side effects. Buried in the article was the accurate statement that the sample
number is too small to draw any conclusions (Mahableshwarkar et al., 2015).
What are the economies of influence that give the appearance, if not
the
reality, of commercialized science in the case of vortioxetine?
Vortioxetine is typical of virtually all new drugs in that the pre-market RCTs
were
all sponsored by the manufacturer. However, congruent with commer-
cialized publication planning, every author in all of the published short term
RCTs, as well as one longer term randomized drug withdrawal study, had
significant commercial ties to the manufacturer, well beyond research fund-
ing (e.g., they were employees, participated on advisory boards, and/or had
received consulting monies or honoraria). These commercial ties are cause
for concern because it has been demonstrated that industry sources of bias in
published and unpublished clinical trial data tend to be subtle, rhetorical, and
Data collection on adverse events was mainly passive via an open-ended question,
“How do you feel?” Such passive methods are known to lead to under-reporting.
Probing for specific adverse effects, which is often done when they are suspected,
is typical in clinical research.
Existing research is not adequate to evaluate safety. The safety of longer-term use
cannot be evaluated in 6-8 week trials. Also, the sample sizes were too small to evaluate
infrequent effects, especially at the approved dose levels. (only 671 patients were
exposed to vortioxetine 20mg in RCTs.
Only two studies used a brief scale, the ASEX, to assess for treatment emergent sexual
dysfunction. Dysfunction on this scale is so broadly defined that the majority of patients
were dysfunctional at baseline where these data were reported, (64.5-71.2% in study
304), making it difficult to detect treatment-related effects. This scale does not measure
change over time or whether a patient believes their medication is affecting their
sexuality.
The FDA review notes that sexual dysfunction increased in a dose-related manner on
vortioxetine. At 20mg/ day the frequency (29%) is similar to that on duloxetine
60mg/day (26%), and double the placebo rate (14%) in pooled short-term trials.
In the majority of studies, withdrawal rates due to adverse events increased in a dose-
related manner. There is little indication from active-controlled RCTs that vortioxetine is
better tolerated or safer than other serotonergic antidepressants, especially at the dose
found to be effective in the US (vortioxetine 20mg/day) (See Table 2).
Figure 4. Why claims of safety and tolerability are not well-supported.
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often go unnoticed by peer reviewers and readers (see, e.g., Heres et al., 2006;
Lundh et al., 2012). For example, results favorable to the manufacturer are
presented in detail, while unfavorable results are often glossed over or
omitted (Heres et al., 2006). Below is a summary of the industry-publishing
relationships of the eight published studies submitted to the FDA and one
additional study submitted to the EMA that was published (Tables 3 and 4).
In eleven of the thirteen publications, the majority of authors were
employees of the manufacturer, and in four of the thirteen published
studies, all authors were company employees.
In all of the trial reports, the authors explicitly thank an employee of the
manufacturer for assistance in the preparation and writing of the
manuscript or note that assistance with preparing and writing the article
was provided by an employee.
In nine of the thirteen published articles, the following issue was dis-
closed: [the manufacturer] was involved in the study design, in the
collection, analysis and interpretation of data, and in the writing of the
report.
The thirteen published studies were published in seven academic jour-
nals. The editors of five of these journals had financial ties to vortiox-
etines manufacturer. As Lexchin and Light (2006) note, commercial bias
resulting from editors financial conflicts of interest can affect the con-
tent of medical journals and the integrity of the scientific record.
The published studies reporting on positive results also do not address the
critical issue of clinical relevance. Addressing this issue is important, not only
because statistical significance may not translate into a clinically meaningful
outcome for trial participants, but also because of the documented concerns
over the generalizability of the results from Phase III RCTs for antidepres-
sants. Typically, only 22% of individuals treated with antidepressants in usual
clinical care meet inclusion criteria for these RCTs (Wisniewski et al., 2009).
Additionally, initial reports of effect sizes in RCTs of medical interventions
tend to shrink in replication studies, increasing the concerns over interpreta-
tion of these small effects (Pereira et al., 2012). Researchers warned that this
can lead to more optimistic outcomes than may exist for real-world
patients (as cited by Borgerson, 2014).
Conclusion
There is increasing evidence that genetic variations may affect how people
metabolize,
tolerate, and respond to medications (Kousar et al., 2015), and
thus an argument can be made for having a variety of drugs available within
the same class. However, prescribers cannot make needed within-class
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Table 3. Vortioxetine study funding and authors disclosures.
FDA trial number Study funding/support Author number Author disclosure to study drug manufacturer
13267A
Boulenger et al.
2014
The authors also thank [H Lunbeck A/S employee] for providing
support in the preparation, revision, and editing of the
manuscript. H. Lundbeck A/S sponsored the study as part
of a joint clinical development programme with the Takeda
Pharmaceutical Company. Lundbeck was involved in the study
design, in the collection, analysis and interpretation of data, in the
writing of the report, and in the decision to submit the paper for
publication.
First Has received grant funding from Lundbeck as well as
honoraria and consultancy fees from Lundbeck
Second Employee of Lundbeck
Third Employee of Lundbeck
12541A
Katona et al. 2012
The authors thank [H Lundbeck A/S employee] for providing
support in the preparation, revision and editing of the
manuscript.”“H. Lundbeck A/S sponsored the study as part
of a joint clinical development programme with the Takeda
Pharmaceutical Company. Lundbeck was involved in the study
design, in the collection, analysis and interpretation of data, in the
writing of the report and in the decision to submit the paper for
publication.
First Has received grant funding from Lundbeck as well as honoraria
and consultancy fees from Lundbeck
Second Employee of Lundbeck
Third Employee of Lundbeck
305
Henigsberg et al.
2012
This study was supported by the Takeda Pharmaceutical
Company, Ltd, as part of a joint clinical development program
with H. Lundbeck A/S. Assistance with writing and manuscript
preparation was provided by [Takeda Pharmaceutical Company
employee].
First Has participated in clinical trials supported by Takeda and
Lundbeck
Second *Has received honoraria for participating in expert panels from
pharmaceutical companies including Lundbeck
Third Employee of Takeda
Fourth Employee of Takeda
Fifth Employee of Takeda
Has been a consultant/advisor for Lundbeck, Takeda
(Continued)
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Table 3. (Continued).
FDA trial number Study funding/support Author number Author disclosure to study drug manufacturer
11492A
Alvarez et al. 2012
This study was sponsored by H. Lundbeck A/S.”“The authors
thank [H. Lundbeck A/S employee] for technical assistance in the
preparation of the manuscript.
First Over the past 2 years, has received consulting and educational
honoraria from Lundbeck; and has participated in clinical trials
sponsored by Lundbeck
Second Over the past 2 years, has received consulting and educational
honoraria from Lundbeck; and has participated in clinical trials
sponsored by Lundbeck
Third Employee of H. Lundbeck A/S, Denmark
Fourth Employee of H. Lundbeck A/S, Denmark
Fifth *Primary Investigator of a grant from Lundbeck on the mechanism
of action of vortioxetine. Also declares having received lecture and
consultancy fees from Lundbeck
11985A
Boulenger et al.
2012
The authors thank [H Lundbeck A/S employee] for providing
support in the preparation, revision and editing of the manuscript.
Lundbeck was involved in the study design, in the collection,
analysis and interpretation of the data, in the writing of the
report and in the decision to submit the paper for publication.
This work was
supported by H Lundbeck A/S.
First Is a consultant for, has received honoraria from and has
conducted clinical research supported by H Lundbeck A/S
Second Employed by H Lundbeck A/S
Third Employed by H Lundbeck A/S
11984A
Baldwin et al. 2012
This study was sponsored by H. Lundbeck A/S as part of a
joint clinical development program with the Takeda
Pharmaceutical Company. Lundbeck was involved in the study
design, in the collection, analysis and interpretation
of data, in the writing of the report, and in the decision to
submit the paper for publication.”“The authors thank [H. Lundbeck
A/S
employee] for providing support in the preparation, revision, and
editing of the manuscript.
First Has received honoraria for educational presentations from H.
Lundbeck A/S, and has acted as a paid consultant to Lundbeck,
and currently holds a research grant (on behalf of his employer)
from Lundbeck. Has accepted paid speaking engagements in
industry-supported satellite symposia or other meetings hosted by
Lundbeck
Second Employed by H. Lundbeck A/S
Third Employed by H. Lundbeck A/S
(Continued)
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Table 3. (Continued).
FDA trial number Study funding/support Author number Author disclosure to study drug manufacturer
303
Jain et al. 2013
This study was sponsored by the Takeda Pharmaceutical
Company Ltd as part of a joint clinical development programme
with
H. Lundbeck A/S. Assistance with writing and manuscript
preparation
was provided by [Takeda Pharmaceuticals employee].
First Has been a consultant for Takeda. Has received research funding
support from Takeda. Has participated in speaker/advisory boards
for Takeda
Second Employee of Takeda Global Research and Development Center
Third Employee of Takeda Global Research and Development Center
Fourth Employee of Takeda Global Research and Development Center
Fifth Has been a consultant/advisor for Lundbeck, Takeda
304
Mahableshwarkar
et al. 2013
This study was funded by the Takeda Pharmaceutical Company,
Ltd as part of a joint clinical development program with
H. Lundbeck A/S.”“Assistance with writing and manuscript
preparation was provided by [name removed], with financial
support from Takeda Pharmaceuticals.
First Employee of the Takeda Global Research and Development Center
Second Employee of the Takeda Global Research and Development Center
Third Employee of the Takeda Global Research and Development Center
14122A**
McIntyre et al. 2014
The authors thank [H. Lundbeck A/S employee] for providing
support in the preparation, revision, and editing of the manuscript.
H. Lundbeck A/S sponsored this study as part of a joint clinical
development program with the Takeda Pharmaceutical company,
Ltd.”“Lundbeck was involved in the study design, in the collection,
analysis and interpretation of data, in the writing of the report, and
in the decision to submit the paper for publication.
First Has received research grant support from Lundbeck. Has also
received speaker/consultant fees from Lundbeck, Takeda.
Second Employee of H. Lundbeck A/S
Third Employee of H. Lundbeck A/S
317
Mahableshwarkar
et al. 2015b
Assistance with writing and manuscript preparation was provided
by Ann C. Sherwood, PhD, of The Medicine Group
and funded by the Takeda Pharmaceutical Company, Ltd, and
H. Lundbeck A/S.
First Employee of the Takeda Development Center Americas
Second Employee of the Takeda Development Center Americas
Third Has been an employee of Takeda Development Center
Fourth Americas Employee of the Takeda Development Center Americas
315
Mahableshwarkar
et al. 2015a
This study was supported by the Takeda Pharma- ceutical
Company, Ltd and H. Lundbeck A/S. The Takeda Pharmaceuti- cal
Company was involved in the design, investigator selection,
conduct of the trial, collection of data, analysis and interpretation,
and writing of the final study report. The authors had full control of
the content of the manuscript.
First Employee of the Takeda Development Center Americas
Second Employee of the Takeda Development Center Americas
Third Employee of the Takeda Development Center Americas
Fourth Was an employee of the Takeda Development Center Americas at
the time the study was conducted
(Continued)
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Table 3. (Continued).
FDA trial number Study funding/support Author number Author disclosure to study drug manufacturer
316
Jacobsen et al.
2015
This study was supported by the Takeda Pharmaceutical Company,
Ltd and H. Lundbeck A/S.”“Takeda and Lundbeck were involved in
the design, investigator selection, conduct of the trial, collection of
data, analysis and interpretation, and writing of the final study
report. The authors had full control of the content of the
manuscript.
First Employee of the Takeda Development Center
Americas
Second Employee of the Takeda Development Center Americas
Third Was an employee of the Takeda Development Center Americas at
the time the study was conducted
Fourth Was an employee of the Takeda Development Center Americas at
the time the study was conducted
Wang et al. 2015 H. Lundbeck A/S sponsored the study as part of a joint clinical
development program with the Takeda Pharmaceutical Company,
Ltd. Lundbeck was involved in the study design, col- lection,
analysis and interpretation of data, writing of the report, and the
decision to submit the paper for publication.
First Has received grant funding, honoraria and consultancy fees from
Lundbeck
Second Employee of Lundbeck
Third Employee of Lundbeck
Fourth Has received honoraria and/or has participated in advisory boards
on behalf of Lundbeck
FCOI = Financial Conflict of Interest; FCOIs listed only include relationships with Lundbeck or Takeda; *Disclosure from article other than vortioxetine study publication; **Study
14122A was reviewed by the European Medicines Agency and was identified as the published study submitted post approval and noted in the EMA report. All other studies were
reviewed by FDA, except for Wang et al. 2015 (no EMA or FDA ID).
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Table 4. Vortioxetine study journals and journal editors financial conflicts of interest.
FDA trial
number Journal Journal FCOI
12541A,
13267A
International Clinical
Psychopharmacology
*Journal editor has received consulting fees or honoraria
from AstraZeneca, Bionevia, BristolMyers Squibb,
GlaxoSmithKline, Johnson & Johnson, Lilly, H. Lundbeck A/S,
Merck & Co. Inc., Ms Science, Merz Pharmaceuticals, Neurim
Pharmaceuticals, Otsuka, Pfizer Inc., Pierre Fabre, Roche
Pharmaceuticals, Sanofi-Aventis, Sepracor Inc., Servier
Laboratories, Synosis, Takeda, Theracos, Transcept, UBC,
Xytis, and Wyeth.
305,
01179516,
01163266
Journal of Clinical Psychiatry *Journal editor is a major stock owner of Healthcare
Technology Stystems, Inc. [sic]; he consults to Dey Pharma,
PGxHealth, Myriad Genetics, and Zynx Health; and is the
principal investigator on an investigator-initiated grant from
Pfızer Pharmaceuticals to Penn State.
*Journal editor is a consultant for Eli Lilly, Pfizer, Best
Practice Project Management, AstraZeneca, Wyeth,
Cyberonics, Novartis, Forest, GlaxoSmithKline, ZARS, Jazz,
Lundbeck, Takeda, and eResearch Technology; has received
research grant funding from Eli Lilly; and has major stock
ownership of Healthcare Technology Systems, Inc.
*Journal is a client of Healthcare Global Village. According
to their website, http://www.hcgv.com/ Healthcare Global
Village is a full service medical communication and
consulting company. We are comprised of physicians,
thought leaders, and education specialists.
11492A, 303,
14122A**
International Journal of
Neuropsychopharmacology
The Editor-in-Chief of this Journal, [Editor Name], serves on
an advisory board for Lundbeck that deals with the
mechanism of action of Lu AA21004. Consequently, he
recused himself from the review process which was handled
by an appropriate Field Editor.
*This is the official journal of CINP. According to their
website http://cinp.org/about-us/ The CINP maintains
partnership and cooperation with the worldwide
pharmaceutical industry
11985A Journal of
Psychopharmacology
*First joint journal editor has received honoraria from
Janssen and Lilly and consulting
fees from Shire.
*First joint journal editor has acted as consultant to
Lundbeck and D&A Pharma
*Second joint journal editor has received grants and/or
honoraria from Astra Zeneca, Biovail, Bristol Myers Squibb,
Eli Lilly, Janssen, Labopharm, Lundbeck/Takeda, Schering-
Plough/Merck, Sepracor, Servier and Wyeth.
11984A European
Neuropsychopharmacology
*Journal
editor holds stocks in TGD and BiolineRx and has
received research grant support and/or travel support and/
or speaker fees and/or consultancy fees from JNJ, Pfizer,
Lundbeck, Teva, BioLineRx, Eli Lilly, Sanofi-Aventis, Roche,
GSK, Servier, Envivo, and Novartis.
FCOI = Financial Conflict of Interest; CINP = Collegium Internationale Neuro-Psychopharmacologicum;
*Disclosure from article other than vortioxetine study publication; **Study 14122A was reviewed by the
European Medicines Agency. All other studies were reviewed by FDA; Bolding added to identify the
commercial ties to the manufacturer of vortioxetine.
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comparisons if there are no trials available comparing older and newer drugs.
Because regulatory agencies only require benefit to be shown over placebo
and not a comparator, current standards for new drug approvals are not
robust enough to help ensure that new drugs show net benefits compared to
existing ones. Moreover, as this brief case study shows, the design choices,
interpretive strategies, and rhetorical devices employed by researchers with
industry ties and published in journals with commercial ties give the reader
the impression that a new antidepressant is safe and well tolerated, when in
fact the data were not collected or analyzed in a way that provides sound
empirical support for this conclusion. Additionally, the data on efficacy are
not reported in the published trials with the caution that is warranted and
that is reflected in the independent meta-analyses. The lowest price for a
months supply of vortioxetine is USD 253.55; the antidepressants used as
active comparators in the RCTsduloxetine and venlafaxineare available
as generics and cost from USD 14.40 to USD 52.25 per month (Goodrx.com,
2015). Thus, the public will be paying up to 17 times more for a drug that
appears to be less efficacious, and is unlikely to be safer or better tolerated
than existing alternatives. Caveat emptor.
We found that publication planning is facilitated by the following
tripartite economies of influence: academe, medical publishing, and industry.
Indeed, the systematic practices that have developed within academic med-
icine (e.g., medical journal editors with ties to drug manufacturers) are
accepted and normative, as are weak regulatory policies (e.g., no requirement
that the manufacturer show evidence of clinical relevance or use patient-
oriented outcome measures). Also, because universities reward faculty (e.g.,
in terms of tenure and promotion) for publications, and yet have limited
oversight of ghostwriting, medical school faculty may find themselves com-
plicit in ghostwriting activities (Shnier et al., 2013, p. 5). These practices
undermine the integrity of academic medicine and its commitment to public
health. As demonstrated in this case study, the economies of influence that
may intentionally and unintentionally produce evidence-biasedrather than
evidence-basedmedicine are varied and complex, and simple transparency
cannot correct this organizational deviance (Hedgecoe, 2014). This is
because the problem is not a bad apple, but rather a bad barrel (Lessig,
2013). Indeed, as long as the pharmaceutical industry controls the produc-
tion of knowledge, the interest of the industry will influence the knowledge
that is produced . . . . [a]nd nothing short of the radical reimagining of the
relationship between research and industry can succeed in eliminating the
distortions of the pharmaceutical industry on the scientific literature (Resnik
and Elliott, 2013). A former editor of the British Medical Journal similarly
noted, [o]nly such a radical step, I think, will stop journals from being
beholden to companies. Instead of publishing trials, journals could concen-
trate on critically describing them (Smith, 2005).
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Thus, genuine reform and restoring integrity in academic medicine will
require policy changes and a paradigm shift.
Neutralizing economies of influence: Solutions for reform
In light of the problems identified in this article, we offer the following
recommendations:
Regulatory bodies should consider the clinical benefit of a new drug in
light of the data on existing similar therapeutic options (Angell, 2004;
Avorn, 2005; Goldacre, 2013). The relative benefit of the new medicine
as compared with existing products should be included in the product
labeling. This policy change would strengthen current regulatory stan-
dards and give physicians a better sense of the relative efficacy and
tolerability of new medications.
All patient-level data submitted during the approval process should be
publically available (Koenig et al., 2015; see also http://www.bmj.com/
open-data) and there should be strict oversight to ensure compliance
with the mandate for transparency. Greater transparency and account-
ability would allow independent researchers to replicate industry-spon-
sored clinical trial data. Additionally, greater transparency would allow
peer reviewers, editors, and clinicians to have the data to make mean-
ingful comparisons of older and newer medications.
Congruent with standards for systematic reviews, the assessment of
treatment outcomes should always be based on the full body of clinical
evidence available, including a thorough assessment of unpublished trial
data (see, e.g., Higgins and Green, 2011). Strengthening standards will
help regulatory bodies make more informed decisions about new drug
approvals.
There should be greater transparency of medical journals commercial
conflicts of interests (e.g., Elliott, 2004). For example, just as authors/
researchers have to declare potential conflicts, so too should medical
journals be required to declare, for each article they publish, relationships
with advertisers, medical communication, or consulting companies that
represent a potential conflict of interest. Increased transparency will allow
readers to assess for the possibility of imbalanced reporting of drug efficacy
and safety.
Regulatory bodies need to develop standards for obtaining, measuring,
analyzing, and reporting AE data in Phase III RCTs (Baciu, Stratton, and
Burke, 2006). These standards should be strictly enforced when the side
effect profile of a class of medications is well known. This change will
better ensure that trials are designed in the publics best interest.
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Regulatory agencies and medical journal editors should require
researchers to provide support for their choice of outcome measures
used in RCTs, identify any concerns noted in the literature about these
measures, and demonstrate that the outcome measures are patient, not
disease, oriented (Shaughnessy and Slawson, 2003). Using patient-
oriented outcome measures will focus attention on clinical, not simply
statistical, significance.
There should be a rebuttable presumption of prohibiting individuals
with industry ties to serve as editors of medical journals (see, e.g.,
Cosgrove and Krimsky, 2012; Doucet and Sismundo, 2008).
Individuals who serve on pharmaceutical or medical device companies
Speakers Bureaus should be prohibited from serving as medical journal
editors. This policy change would create a better firewall between com-
mercial interests and the dissemination of clinical trial data.
Key messages
Vortioxetine, a serotonergic antidepressant, was approved by the FDA and
EMA in late 2013.
Through a critique of the clinical trials submitted to these regulatory agen-
cies, we identify the ways in which relationships among academe, publishing,
and industry can facilitate commercial bias in how drug efficacy and safety data
are obtained, interpreted, and presented to regulatory bodies and prescribers.
We show the economies of influence that may intentionally and unintentionally
produce evidence-biasedrather than evidence-basedmedicine.
Acknowledgments
We would like to thank Emily Wheeler, Shannon Peters, Justin Karter, Akansha Vaswani,
Chris Schuck, Madeline Brodt, and Bob Whitaker for their assistance and for their helpful
comments and feedback.
Disclosure
L.C. is the principal investigator for an RO3 grant funded by AHRQ: R03HS022940-01A1. L.
C. has no industry conflicts of interest. No other authors report any conflicts of interest.
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... Yet industry payments to journal editors are common and often large, particularly for certain subspecialties (Haque et al., 2018;Lui et al., 2017). A 2019 review of top tier (and often highly cited) medical journals found that the average direct payments to physician-editors to these journals was $55,157 per year and that pharmaceutical companies additionally paid an average of $175,282 per year in indirect payments (e.g., to the physician-editor's institution) for research (Wong et al., 2019; see also Cosgrove et al., 2016). ...
... Therefore, being knowledgeable about pharmacodynamics, pharmacokinetics and the efficacy and safety of psychotropic drugs is critically important for rational, evidence-based practice (Lyons et al., 2004). Unfortunately, it has been repeatedly shown that academicindustry relationships have a corrupting influence on evidence-based practice (Cosgrove et al., 2016;Institute of Medicine, 2011;Lundh et al., 2018;Perlis et al., 2005) in all of medicine, including psychiatry. Conflicts of interest occur when an author's professional judgment is at risk of being influenced by a secondary outcome, including financial gain. ...
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While most medical journals require disclosures of industry payments to authors and editors, there is no requirement for textbooks. In this study we evaluated nine well-known psychopharmacology textbooks to identify payments to their writers and editors. Two-thirds of the textbooks had at least one editor or author who received personal payments from one or more pharmaceutical companies, for a total of 11,021,409 USD paid to 11 of 21 editors/authors over a seven-year period. Much of this money was paid to a single author but 24% of the writers received over 75,000 USD each over this time period. There are several psychopharmacology textbooks authored by writers without apparent financial conflicts of interest. Just as with medical journals, medical textbooks should be transparent about payments made to their authors and editors.
... Concerns about the reliability of evidence, especially in terms of its trustworthiness are nothing new. [1][2][3][4] Even high-quality randomized controlled trials (RCTs) supported by robust evidence can be reversed, further proving the fluidity of evidence. 5 For example, although aspirin (ASA) is widely prescribed for the primary prevention of cardiovascular disease, 6,7 interpretations of the ARRIVE trial 8 (and other recently published RCTs) suggest this practice is no longer justified. ...
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Background: Evidence-Based Medicine is built on the premise that clinicians can be more confident when their decisions are grounded in high-quality evidence. Furthermore, evidence from studies involving patient-oriented outcomes is preferred when making decisions about tests or treatments. Ideally, the findings of relevant and valid trials should be stable over time, that is, unlikely to be reversed in subsequent research. Objective: To evaluate the stability of evidence from trials relevant to primary healthcare and to identify study characteristics associated with their reversal. Methods: We studied synopses of randomized controlled trials (RCTs) published from 2002 to 2005 as "Daily POEMs" (Patient Oriented Evidence that Matters). The initial evidence (E1) from these POEMs (2002-2005) was compared with the updated evidence (E2) on that same topic in a summary resource (DynaMed 2019). Two physician-raters independently categorized each POEM-RCT as (i) reversed when E1 ≠ E2, or as (ii) not reversed, when E1 = E2. For all "Evidence Reversals" (E1 ≠ E2), we assessed the direction of change in the evidence. Results: We evaluated 408 POEMs on RCTs. Of those, 35 (9%; 95% confidence interval [6-12]) were identified as reversed, 359 (88%) were identified as not reversed, and 14 (3%) were indeterminate. On average, this represents about 2 evidence reversals per annum for POEMs about RCTs. Conclusions: Over 12-17 years, 9% of RCTs summarized as POEMs are reversed. Information alerting services that apply strict criteria for relevance and validity of clinical information are likely to identify RCTs whose findings are stable over time.
... [14][15][16][17] By highlighting the discrepancies among different sources of data for the same trials, primarily publications (when available) and regulatory documents, other assessments have led to a fundamental reappraisal of the properties of drugs and biologics. [18][19][20][21][22][23][24][25][26][27][28][29][30] More detail of each of these assessments is provided in Figure 1 (adapted from Jefferson et al. 31 ). ...
... In addition to choosing certain lines of research over others, scientific ignorance also emerges through the selection of different paths within the research process. As Kevin Elliott (2013Elliott ( , 2015 identifies, selective ignorance also stems from choices about how to study a complex topic in some way rather than others, what sort of information to collect, and how to disseminate such information (see also, Cosgrove et al. 2016;Holman & Bruner 2015;Sismondo 2009). In this sense, selecting a line of research over others is just one decision in the scientific process among many, inevitably contributing to the production of scientific ignorance. ...
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The aim of the paper is to clarify the concept of scientific ignorance: what is it, what are its sources, and when is it epistemically detrimental for science. I present a taxonomy of scientific ignorance, distinguishing between intrinsic and extrinsic sources. I argue that the latter can create a detrimental epistemic gap, which have significant epistemic and social consequences. I provide three examples from medical research to illustrate this point. To conclude, I claim that while some types of scientific ignorance are inevitable and even desirable, other types of scientific ignorance are epistemically and ethically flawed and should be prevented.
... Unsurprisingly, conflicts of interest in biomedical research are rampant, and the effects of such conflicts on the reliability of biomedical research far from harmless (Li et al. 2019;Khan et al. 2018;Cosgrove et al. 2016). Although some evidence shows that studies with for-profit sponsors are not of worse quality than those funded by public money, multiple studies have shown that industry-sponsored trials are often designed, analyzed, and reported in ways that favor sponsors (Lundh et al. 2018;Schott et al. 2010;Flacco et al. 2015;Lathyris et al. 2010). ...
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The growing commercialization of scientific research has raised important concerns about industry bias. According to some evidence, so-called industry bias can affect the integrity of the science as well as the direction of the research agenda. I argue that conceptualizing industry’s influence in scientific research in terms of bias is unhelpful. Insofar as industry sponsorship negatively affects the integrity of the research, it does so through biasing mechanisms that can affect any research independently of the source of funding. Talk about industry bias thus offers no insight into the particular epistemic shortcomings at stake. If the concern is with the negative effects that industry funding can have on the research agenda, conceptualizing this influence as bias obscures the ways in which such impact is problematic and limits our ability to offer solutions that can successfully address the concerns raised by the growing role of private funding in science.
... In fact, one-agomelatine-is not approved for use in the United States because of documented cases of liver impairment and damage (Gahr, 2014). Independent (i.e., nonindustry-funded) researchers who reexamined the clinical trial data for vortioxetine found that the generic comparator drugs were actually more efficacious in a number of the trials (Cosgrove, Vannoy, Mintzes, & Shaughnessy, 2016;Meeker, Herink, Haxby, & Hartung, 2015;Pae et al., 2015). Cipriani et al. (2018) rated 82% of the 522 trials reviewed as having a moderate to high risk of bias. ...
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Since the approval of fluoxetine in 1987, there have been contentious debates about whetherantidepressants “work.” A recent meta-analysis on the efficacy and tolerability of antide-pressants reinvigorated debates about their effectiveness— debates that have importantimplications for both research and practice in humanistic psychology. This article brieflydiscusses the findings and identifies the limitations of this meta-analysis, and we show thatusing psychopharmacology as a routine first response is not evidence based and incongruentwith the basic principles of humanistic psychology. Additionally, we argue that the question“do antidepressants work?” is reductive and undermines our responsibility to individuals whoare suffering from emotional distress. Responding to the Cipriani et al. (2018) study from ahumanistic lens (a) deepens our appreciation for the lived experience of individuals diag-nosed with depression and our responsibility to them, (b) complicates assumptions about theontological status of “depression,” and (c) enhances collaborative, client-centereddecision-making.Keywords:depression, antidepressants, humanistic psychology, client-centered care
... There is anecdotal evidence indicating that authors who have relationships with industry tend to publish more positive results, which may favor the industry [2][3][4]. Negative events have highlighted the need to safeguard scientific integrity and public health. Stakeholders should make efforts to prevent bias caused by COIs and furthermore to discourage ill-considered relationships resulting in COIs [5]. ...
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Importance: Conflicts of interest (COI) disclosure policies are critical to enhancing the integrity of research. However, it is unclear how Chinese medical journals interpret and enforce such policies. Objectives: The goal of this investigation is to determine the current status of COI disclosure policy enforcement in Chinese medical journals and to promote comprehensive COI policies. Methods: In this cross-sectional study conducted from September 1st to October 29th 2017, journal instructions, websites and print issues of journals indexed by the Core Journals of China (version 2014), in the medical and health sector, were reviewed to identify whether COI disclosure policies existed and how complete these policies were. Results: Of 248 eligible journals, 78 (31%) mentioned COI policies; 9 (4%) applied standardized disclosure forms; 18 (7%) required disclosure statements in articles; 4 (2%) mentioned policy bases; none validated disclosed COIs; 2 (1%) mentioned how they dealt with breaches; 18 (7%) involved the management of disclosed COIs; and 62 (25%) and 55 (22%) noted financial and nonfinancial COIs, respectively. Seventy-eight journals (31%) mentioned COIs in research and authors' obligation towards disclosure; 2 (1%) and 6 (2%) mentioned family members' and institutional COIs, respectively. Twenty-two and 11 journals mentioned at least one form of financial and nonfinancial COI type in research, respectively. Seven journals (3%) required disclosure of the source of financial support in research, but no journals mentioned the amount of support. Seven (3%) and 12 (5%) journals mentioned COIs in the editorial process and peer-review, respectively. Clinical journals (45%) paid more attention to COI policies than non-clinical journals. Conclusions: Approximately one-third of Chinese medical journals had COI policies, and of the journals that mentioned financial COIs most required nonfinancial COIs. However, the extent to which journals implemented COI policies was insufficient. There is a generic lack of standardized disclosure forms and management of COIs in most journals. The subject and details of COIs involved in the editorial and peer-review process received less attention than those in research.
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Introduction: The systematic review of biomedical ghostwriting has proven challenging due to problems in consistency and in study design. Moreover, authorship guidelines established by the International Committee of Medical Journal Editors (ICMJE) may have inadvertently created opportunities to potentiate ghostwriting. Given continued interest in ghostwriting by the International Society of Medical Publication Professionals (ISMPP) and other organizations, we undertook an analysis of ghostwriting in the biomedical literature. Methods: We searched PubMed (search terms: ghost writ*, ghostwrit*, ghost writer, ghostwriter, ghostwriting, and ghost writing). Results, including abstracts, were reviewed for relevance (relationship to ghostwriting in biomedical journals) to aid in removal of inapplicable work and duplicate publications. After review, we consolidated expert opinions for publication professionals. Results: Overlap was poor across search terms; of 181 unique papers identified; most (112/181) were opinion pieces. An increasing number of papers are using the term “ghostwriting” to describe genetics as well as diverse phenomena of misattributed authorship, including “ghost authorship.” Eight primary studies and 1 systematic review of ghostwriting incidence were identified, reporting prevalence ranging from <1% to 91%, in varied settings using differing methods and definitions of ghostwriting. Suggestions for avoiding ghostwriting include early consensus building and better definitions of authorship among manuscript teams. Discussion: The prevalence and definition of ghostwriting remain unclear. Increased transparency and auditable authorship practices that align with specific guidelines may aid in the avoidance of ghostwriting. In addition, MeSH or clearer indexing terms may be helpful to separate usages of ghostwriting in scientific settings (e.g., genetic research) versus biomedical publishing.
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Objectives To reanalyse SmithKline Beecham’s Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine. Design Double blind randomised placebo controlled trial. Setting 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. Participants 275 adolescents with major depression of at least eight weeks in duration. Exclusion criteria included a range of comorbid psychiatric and medical disorders and suicidality. Interventions Participants were randomised to eight weeks double blind treatment with paroxetine (20-40 mg), imipramine (200-300 mg), or placebo. Main outcome measures The prespecified primary efficacy variables were change from baseline to the end of the eight week acute treatment phase in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) at acute endpoint. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapse during the maintenance phase. Adverse experiences were to be compared primarily by using descriptive statistics. No coding dictionary was prespecified. Results The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group. Conclusions Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.
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Vortioxetine is the first mixed serotonin agonist and antagonist antidepressant approved in the US. We sought to evaluate all published and unpublished data available to determine the efficacy and harms of vortioxetine in adults with major depressive disorder. We used a predefined search strategy of MEDLINE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Drugs@FDA to identify studies evaluating vortioxetine in the acute treatment of major depressive disorder. Only randomized controlled trials (RCTs) that provided results on relevant clinical efficacy and safety outcomes were included. Study quality was assessed and results were pooled using mixed effect meta-analyses where applicable. We identified 11 RCTs with 6,145 participants meeting inclusion criteria (eight were published and three were unpublished). The trials did not exceed 8 weeks in duration. The response rate with vortioxetine was significantly higher for 1-mg (relative risk (RR) = 1.91; 95% confidence interval (CI) 1.36 to 2.69), 5-mg (RR = 1.33; 95% CI 1.10 to 1.61), 10-mg (RR = 1.42; 95% CI 1.21 to 1.67), and 20-mg doses (RR = 1.58; 95% CI 1.19 to 2.08) compared to placebo. Remission rates were significantly higher for the 10-mg group (RR = 1.45; 95% CI 1.18 to 1.77) and the 20-mg group (RR = 1.68; 95% CI 1.19 to 2.37) compared to placebo. Meta-regression of dose on the log odds ratio of response was not statistically significant (β = 0.01; P = 0.46). Vortioxetine response rates were lower than active serotonin and norepinephrine reuptake inhibitor (SNRI) comparators for the 5-mg (RR = 0.88; 95% CI 0.80 to 0.98), 15-mg (RR = 0.78; 95% CI 0.68 to 0.90), and 20-mg (RR = 0.82; 95% CI 0.72 to 0.94) doses. The most common adverse events were nausea and vomiting which increased in frequency with higher doses. Vortioxetine was significantly more effective than placebo for acute treatment of major depressive disorder (MDD). Although treatment effect estimates varied substantially between studies, a dose effect was not observed. Vortioxetine does not appear to be more effective, and is potentially less effective, than an SNRI. PROSPERO CRD42013006198 .
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In the wake of publicity and congressional attention to drug safety issues, the Food and Drug Administration (FDA) requested the Institute of Medicine assess the drug safety system. The committee reported that a lack of clear regulatory authority, chronic underfunding, organizational problems, and a scarcity of post-approval data about drugs' risks and benefits have hampered the FDA's ability to evaluate and address the safety of prescription drugs after they have reached the market. Noting that resources and therefore efforts to monitor medications' risk-benefit profiles taper off after approval, The Future of Drug Safety offers a broad set of recommendations to ensure that consideration of safety extends from before product approval through the entire time the product is marketed and used. © 2007 by the National Academy of Sciences. All rights reserved.
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Vortioxetine (Lu AA21004) is an antidepressant with a mechanism of action thought to be related to a combination of 2 pharmacologic actions: direct modulation of several receptors and inhibition of the serotonin transporter. To evaluate the efficacy of vortioxetine 10 and 20 mg once daily in outpatients with major depressive disorder. This 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted from July 2010 to January 2012 among adults with a primary diagnosis of recurrent major depressive disorder (DSM-IV-TR). Eligible subjects were randomized in 1:1:1 ratio to 1 of 3 treatment arms: vortioxetine 10 mg, vortioxetine 20 mg, or placebo once daily for 8 weeks. Subjects who completed the 8-week trial entered a 2-week blinded discontinuation period to assess potential discontinuation symptoms. The primary endpoint was the least squares mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline. Key secondary outcomes were analyzed in the following prespecified sequential order: MADRS response (≥ 50% decrease from baseline in total score), Clinical Global Impressions-Improvement score, change from baseline in MADRS total score in subjects with baseline Hamilton Anxiety Rating Scale score ≥ 20, MADRS remission (total score ≤ 10), and change from baseline in Sheehan Disability Scale total score (all at week 8). A total of 462 subjects were randomized to placebo (n = 157), vortioxetine 10 mg (n = 155), and vortioxetine 20 mg (n = 150). Mean (SE) reductions from baseline in MADRS total score (week 8) were -10.77 (± 0.807), -12.96 (± 0.832), and -14.41 (± 0.845) for the placebo, vortioxetine 10 mg (P = .058 vs placebo), and vortioxetine 20 mg (P = .002 vs placebo) groups. MADRS response/remission was achieved in 28.4%/14.2%, 33.8%/21.4%, and 39.2%/22.3% of subjects, respectively, in the 3 groups. Only MADRS response for vortioxetine 20 mg significantly separated from placebo (P = .044). Treatment was well tolerated, with the most frequently reported adverse events consisting of nausea, headache, diarrhea, and dizziness. Vortioxetine 20 mg significantly reduced MADRS total score at 8 weeks in this study population. Overall, vortioxetine was well tolerated in this study. ClinicalTrials.gov identifier: NCT01163266. © Copyright 2015 Physicians Postgraduate Press, Inc.
Article
Background: This 8-week, randomized, double-blind, placebo-controlled study, conducted August 2010-May 2012 in the United States, evaluated the safety and efficacy of vortioxetine 10 mg and 15 mg in patients with major depressive disorder (MDD). The mechanism of action of vortioxetine is thought to be related to direct modulation of serotonin (5-HT) receptor activity and inhibition of the serotonin transporter. Method: Adults aged 18-75 years with MDD (DSM-IV-TR) and Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 26 were randomized (1:1:1) to receive vortioxetine 10 mg or 15 mg or placebo once daily, with the primary efficacy end point being change from baseline at week 8 in MADRS analyzed by mixed model for repeated measures. Adverse events were recorded during the study, suicidal ideation and behavior were assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS), and sexual dysfunction was assessed using the Arizona Sexual Experience (ASEX) scale. Results: Of the 1,111 subjects screened, 469 subjects were randomized: 160 to placebo, 157 to vortioxetine 10 mg, and 152 to vortioxetine 15 mg. Differences from placebo in the primary efficacy end point were not statistically significant for vortioxetine 10 mg or vortioxetine 15 mg. Nausea, headache, dry mouth, constipation, diarrhea, vomiting, dizziness, and flatulence were reported in ≥ 5% of subjects receiving vortioxetine. Discontinuation due to adverse events occurred in 7 subjects (4.4%) in the placebo group, 8 (5.2%) in the vortioxetine 10 mg group, and 12 (7.9%) in the vortioxetine 15 mg group. ASEX total scores were similar across groups. There were no clinically significant trends within or between treatment groups on the C-SSRS, laboratory values, electrocardiogram, or vital sign parameters. Conclusions: In this study, vortioxetine did not differ significantly from placebo on MADRS total score after 8 weeks of treatment in MDD subjects. Trial registration: ClinicalTrials.gov identifier: NCT01179516.
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Variations in drug metabolizing genes are known to have a clinical impact on AED therapy. We genotyped normal and epileptic patient cohorts of monoethnic population of Kashmir valley for CYP2C9 gene and allelic polymorphism and investigated the effect of CYP2C9*2 and *3 polymorphism on the Pharmacokinetic and therapeutic and/or adverse pharmacodynamic responses to Phenytoin in the idiopathic epilepsy patients. PCR-RFLP methods were used for genotyping of 121 normal controls and 92 idiopathic epilepsy patients for CYP2C9*2 and *3 polymorphism, the results were validated by direct sequencing. Phenytoin pharmacokinetic (PK) analysis in idiopathic epilepsy patients was done using a validated EMIT assay technique. Pharmacodynamic analysis was done by evaluating clinical response to phenytoin therapy and ADR monitoring. The respective frequencies of CYP2C9 *1, *2, and *3 alleles were 64%, 6.6%, 29.3%, and 58%, 9.8%, 32.6% in controls and idiopathic epilepsy patients from Kashmir valley. PK analysis revealed that AUC0-4 was a better surrogate biomarker of CYP2C9 metabolizer status compared to C4 and C0 concentrations alone. A comparison of "phenytoin response categories" among CYP2C9 Wild and Heterozygous groups did not reveal any significant difference between the groups (p = 0.3800). CYP2C9* 3 was the most frequent mutant allele found in healthy controls and idiopathic epilepsy patients of ethnic Kashmiri population. CYP2C9 genotype based phenytoin therapy is highly relevant in Kashmiri population due to a high incidence of genetic variations associated with therapeutic and adverse responses to phenytoin. Phenytoin AUC0-4 tends to correlate better with genetic polymorphism of CYP2C9.
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Focusing on the high-profile drug disaster at London's Northwick Park Hospital in 2006, this article explores how such an event can be seen as an example of organizational deviance co-constructed between the company running the research and the research ethics committee which approved the trial. This deviance was the result of the normalization of a specific dosing practice in the broader regulatory field, allowing the researchers and regulators to take a risky dosing strategy for granted as best practice. Drawing on the work of Diane Vaughan, this article uses interview data with researchers and members of the research ethics committee concerned as well as documentary material, to show how work group cultures between regulators and those they are intended to oversee are maintained, and how the culturally embedded assumptions of such work groups can result in organizational and regulatory deviance.
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Objective This randomized, double-blind 8 week study compared the efficacy and tolerability of fixed-dose treatment with vortioxetine (10 mg/day) and venlafaxine extended release (XR) (150 mg/day) in major depressive disorder (MDD) patients. Research design and methods Patients aged 18–65 years with a primary diagnosis of recurrent MDD, a Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥26 and a Clinical Global Impression–Severity (CGI-S) score ≥4 were randomized (1:1) to treatment with either vortioxetine or venlafaxine XR. The primary endpoint was change from baseline to Week 8 in MADRS total score (analysis of covariance [ANCOVA], full-analysis set [FAS], last observation carried forward [LOCF]), using a non-inferiority margin of +2.5 points. Pre-specified secondary endpoints included MADRS response and remission rates, anxiety symptoms (HAM-A), CGI, overall functioning (SDS), and health-related quality of life (Q-LES-Q). Clinical trial registration This study (SOLUTION) has the www.ClinicalTrials.gov identifier: NCT01571453. Results On the primary efficacy endpoint at Week 8, non-inferiority was established with a difference of −1.2 MADRS points in favor of vortioxetine (95% CI: −3.0 to 0.6). The MADRS total score decreased (improved) from 32.3 ± 4.6 at baseline to 13.6 ± 9.6 (vortioxetine: n = 209) and from 32.3 ± 4.5 to 14.8 ± 10.4 (venlafaxine XR: n = 215) (FAS, LOCF). At Week 8, the HAM-A and SDS total scores, CGI and Q-LES-Q scores, and response and remission rates demonstrated similar improvement for vortioxetine and venlafaxine XR, with remission rates (MADRS ≤10) of 43.1% (vortioxetine) versus 41.4% (venlafaxine XR) (LOCF). Fewer vortioxetine than venlafaxine XR patients withdrew for any reason (18.0% versus 27.4%) or for adverse events (6.6% versus 13.7%). The most frequent adverse events (≥5%) for both treatments were nausea, dizziness, headache, and dry mouth. In addition, accidental overdose, decreased appetite, constipation and insomnia were reported by (≥5%) of patients treated with venlafaxine XR. Limitations The inclusion and exclusion criteria may limit the generalizability of the study. Since patients with a history of lack of response to venlafaxine XR were excluded from this study, there is a selection bias in favor of venlafaxine XR. Conclusion Vortioxetine was at least as efficacious as venlafaxine XR and was safe and better tolerated than venlafaxine XR.
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Clinical research has at least three problematic features: it tends to be redundant, secretive, and isolated. Research with these features not only wastes resources and causes harm, it also fails to meet a basic ethical requirement of research: scientific validity. According to a recent editorial in the BMJ, bioethicists and members of research ethics committees have been "notable by their absence" among those exposing persistent problems with clinical research and proposing solutions (Chalmers, Glasziou, and Godlee, BMJ 346, 2013, f105). In this paper I offer a theoretical diagnosis for the complicity of bioethicists and research ethics committees in these ongoing problems, as well as a partial solution in the form of a modified ethical requirement of scientific integrity.