Transcript Medical journals are an extension of the marketing arm of

Medical journals are an
extension of the
marketing arm of drug
companies
Richard Smith
Chief executive, United Health Europe
Formerly editor BMJ
Agenda
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Editors are all at it
Observations on the drug industry
Advertising
Trials
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Mostly drug company funded
Rarely produce results unfavourable to the company
Easy to get the results you want
Manipulating the journals
Four stories of manipulation
Reprints
Supplements
“A better relationship?”
Richard Horton, editor,
Lancet
• “Journals have devolved into
information laundering
operations for the
pharmaceutical industry”
• New York Review of Books,
March 11, 2004
Marcia Angell, former
editor, NEJM
• “ [The pharmaceutical industry] has moved
very far from its original high purpose of
discovering and producing useful new
drugs. Now primarily a marketing machine
to sell drugs of dubious benefit, this
industry uses its wealth and power to coopt every institution that might stand in its
way, including the U.S. Congress, the Food
and Drug Administration, academic
medical centers, and the medical
profession itself."
Jerry Kassirer, former
editor, NEJM
• “In On the Take, Dr. Jerome Kassirer offers
an unsettling look at the pervasive payoffs
that physicians take from big drug
companies and other medical suppliers,
arguing that the billion-dollar onslaught of
industry money has deflected many
physicians' moral compasses and directly
impacted the everyday care we receive
from the doctors and institutions we trust
most.”
• OUP promotional blurb
Editors of PLOS Medicine:
“Prescription for a healthy journal”
• “We have decided not to be part of the cycle of
dependency that has formed between journals
and the pharmaceutical industry, an industry
that focuses overwhelmingly on the most
profitable drugs, thus sidelining many of the
world's health problems. Medical journals have
allowed their interests to become aligned with
those of the pharmaceutical industry by printing
advertisements for drugs, publishing trials
designed by drug companies' marketing
departments, and making profits on reprints used
as marketing tools.”
The drug industry
• Has invented virtually all the new drugs in the past
50 years--although Mrcia Angell says that they
“feed off” public investment in science
• Hugely profitable and politically powerful
• Global
• Business model—new drugs plus increased revenue
from existing drugs—failing: productivity crisis
(fewer new drugs; marginal benefits) plus political
pressure on price increases
• “Drug companies turning into banks.” Charles
Medawar
• Response: more marketing; perhaps mergers to
create “monopolies” around
The drug industry
• US based companies spent $15.7
billion on promotion in 2000
• Since 1995 research staff down by
2%, marketing staff up by 59%
• A fifth of staff are researchers but
two fifth are marketing staff
• Industry spends about $10 000 per
doctor on promotion
Advertising
• In most countries drug companies can advertise
only to doctors
• Lucrative market for doctor only publications paid
for entirely by advertising
• Many free publications to doctors—making them
reluctant to pay for anything
• Major journals receive a substantial income from
drug advertising—and most have copies that
circulate free paid for by drug advertising—or
sponsored subscriptions, some with false covers
• Makes them nervous about upsetting advertisers—
hard to quantify that nervousness
Advertising
• The ROI on advertising in
encouraging doctors to
prescribe particular drugs is
greater than that for drug reps
• The advertising is often
misleading
Study in the Annals of
Internal Medicine
• 109 ads from 10 major journals
• Reviewed by two physicians from the
relevant specialty and a clinical
pharmacist against FDA guidelines
• Information on efficacy and side
effects unbalanced in 40%
• Would have recommended against
publication in 28%; substantial
revision in a third
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Wilkes MS, Doblin BH, Shapiro MF. Pharmaceutical advertisements in leading medical
journals: experts' assessments. Ann Intern Med 1992;116: 912-9.
Spanish study
• 264 different advertisements for antihypertensive
drugs and 23 different advertisements for lipid
lowering drugs selected from six Spanish medical
journals
• Two reviewers looked at 102 references
• In 44% of ads the promotional statement was not
supported by the reference—most commonly
because the slogan recommended the drug in a
patient group other than that assessed in the study
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Villanueva P, Peiro S, Librero J, Pereiro I. Accuracy of pharmaceutical
advertisements in medical journals. Lancet. 2003;361: 27-32.
Should journals carry
advertising?
• No
– Misleading
– Distorts prescribing patterns
– Demeans the journal, reducing its credibility
• Yes
– Provides income for journal and may carry fewer
strings than other sources (for example, from
owners)
– Doctors discount advertising
– Doctors will receive promotional messages
anyway and at least ads are better than what
drug reps may say behind closed doors
Should journal peer review
ads?
• Yes
– Many are known to be misleading
– Reduces credibility of the journal to publish
misleading ads
– Distorts prescribing, bad for patients
• No
– Doctors discount advertising
– Tight regulation (at least in the UK)
– Hard to do properly (and peer review is weak
anyway)
– Better to use resources on the journal itself
– Readers can criticise advertisements
Other deals available to
advertisers
• Favourable editorial mention in exchange
for an ad
• Will publish a particular paper if
advertisers place an ad
• Ad alongside paper
• Tell advertisers what will be in the journal
• “Advertorials”
• Product news
• Keep out unfavourable studies
• Ads on editorial pages, false covers,
messages direct to individual readers
Trials in journals
• Much more valuable to companies
than advertisements (many other
outlets for ads)
• Credibility of the journal attached—
the opposite of being discounted
• Worldwide distribution
• Possibly massive media coverage
Two thirds of trials in major journals
are funded by the drug industry (Egger M,
et al, BMJ 2001; 323: 773)
Journal
Total trials
% drug trials
AIM
20
65
JAMA
47
64
Lancet
82
67
NEJM
83
74
BMJ
48
31
Companies get the results
they want
• Study of 56 studies of non-steroidal
anti-inflammatory drugs
• Not one was unfavourable to the
company
• All showed the manufacturer’s drug
to be as good as the comparison or
better in terms of efficacy or toxicity
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Rochon PA, Gurwitz JH, Simms RW, Fortin PR, Felson DT, Minaker KL, et
al. A study of manufacturer supported trials of non-steroidal antiinflammatory drugs in the treatment of arthritis. Arch Intern Med
1994;154: 157-63.
Companies get the results
they want
• 30 studies compared studies funded by the
pharmaceutical industry with results of
studies funded from other sources
• Five of the studies looked at economic
evaluations and in every study the results
were favourable to the pharmaceutical
company
• 16 studies looked at clinical trials or metaanalyses, and 13 had outcomes favourable
to the companies
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Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and
research outcome and quality: systematic review. BMJ 2003; 326: 1167-70.
Companies get the results
they want
• Overall studies funded by companies
four times more likely to have results
favourable to the sponsor than studies
funded by others
• 13 of the studies examined the quality
of the research
• None found the quality of drug company
sponsored studies to be inferior
• 4 found that the research funded by the
industry was of superior quality
Why do companies get the
results they want?
• Hypothesis 1: companies selectively fund
research on better drugs. No.
• Hypothesis 2: Quality lower not in the
methods but in the questions asked.
• Hypothesis 3: Companies make
inappropriate comparisons—comparing
their drugs with poor drugs or drugs used
at the wrong dose.
• Hypothesis 4: Publication bias in that
favourable studies are more likely to be
published—by companies or journals
The methods of HARLOT
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13 methods to get the results you want
Trial against placebo
Trial against treatment known to be inferior
Trial against low dose of competitor
Trial against high dose of competitor (to give
advantages on toxicity)
• Equivalence or non-inferiority trial that is too
small to show a difference from competitor
drug
• Use multiple endpoints and select the ones
that give positive results
• Subgroup analyses and select positive results
Publishing strategies
• Suppress (don’t write up) negative studies
• Publish positive studies more than once—perhaps
in supplements
• Do multicentre trial and publish results of individual
centres—perhaps selectively
• Publish different outcome measures at different
times
• Publish different follow periods at different times—
3 month results, one year, two year
• Publish positive results in major journals and
negative or neutral results in minor journals
• Combine results of trials in ways that are
favourable
Odansetron story
• 84 trials that included information on 11
980 patients
• In reality only 70 trials and 8645 patients
(17% of the studies had been published
more than once and the number of patients
had been inflated by 28%)
• Impossible to tell from published studies
• Four pairs of identical trials were
published by completely different authors
without any common authorship
(Misconduct)
Effectiveness of odansetron
Cox-2 story
• The three month results of the CLASS study
published in JAMA in 2000 shows that Celebrex is
safer than NSAIDs
• August 2001 the Washington Post reports that the
FDA had the full results of the CLASS study, which
contradicted the JAMA resulys
• The JAMA study had many problems
• Pfizer continues to use reprints of the JAMA paper
to promote the drug
• Many doctors are unaware of the trial being
dicredited
Cox-2 story
• The VIGOR study reported in the NEJM in 2000
showed rofecoxib (Vioxx) to be safer than an NSAID
but also showed cardiovascular toxicity
• Merck, the manufacturers, proposed that the result
was explained by the NSAID protecting against
heart disease
• Four years later the drug has been withdrawn
because a long term placebo controlled trial has
confirmed the cardiovascular toxicity
• Question: Do all Cox-2 inhibitors have these
effects?
CLASS results in JAMA and
with the FDA
The hormone
replacement therapy
• Many observational studies suggested
that HRT reduced coronary artery
disease
• “Rough and ready” meta-analysis of
randomised trials suggested that HRT
actually increased cardiovascular events
• Torrent of abuse from the drug industry
• A major trial and huge observational
study show that HRT does indeed
increase cardiovascular events
Observational studies of coronary artery
disease after hormone replacement therapy
A story
• Study A—compares drugs x and y; results
showing x better than y published in a
major journal; results showing y better
than x on other (clinically more important)
outcome measures not published
• Study B—x no better than y; not published
• Study C—combines studies A and B (and
shows x better than y) published in a major
journal
Reprints
• Enormously lucrative to journals;
companies may buy $1m worth—70% profit
margin
• A major source of revenue for journals
publishing trials
• Handed out to doctors—selectively of
course; not read, but journal brand adds
lustre to selling message
• Major conflict of interest for journals:
“publish this paper or lay off six editors”
Supplements
• A major source of income for some second tier
journals
• Often include papers presented at sponsored
symposia—often around one drug
• Studies often previously published in some way
• Studies selectively published
• Accompanied by opinion pieces by prominent
doctors (opinion leaders in marketing jargon); the
doctors are very well paid (? bought)
• The person who organised the symposium may be
the editor
• Standards of supplements shown to be inferior to
standards of parent journals (which may
themselves be low)
Sponsored supplements
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The number of symposiums published per year increased
steadily from 1966 through 1989
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42% had a single pharmaceutical company as the sponsor
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Sponsored symposia
– more likely to have misleading titles
– more to use brand names
– less likely to be peer-reviewed in the same manner as other
articles in the parent journal
– Of the 161 symposiums that focused on a single drug
• 51% concerned unapproved therapies
• 14 percent concerned drugs classified as bringing
important therapeutic gains
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Bero LA, Glabraith A, Rennie D. The publication of sponsored symposiums in medical journals.
N Engl J Med 1992;327:1135-40.
“Solutions”
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Public funding of head to head trials
Registers of trials
Protocol reviews
Role of sponsor made clear
Journals decline to publish trials unless
researchers control decision to publish
• Journals don’t publish trials—rather results
are made available in full on regulated
websites together with protocols
Conclusion
•Medical journals are
an extension of the
marketing arm of
drug companies
•Do you agree?