Transcript Conflicts of Interest and the Industry Funding of Research

Ethics and Research Design:
Industry influences on
research
“Dancing with the porcupine”
• “The duty of universities is to seek truth.
The duty of pharmaceutical companies is
to make money for their shareholders…At
times, institutional imperatives are bound
to conflict.”
– Lewis et al., CMAJ (2001)
• But if “evidence” is designed to promote a
company’s product, what implications
does this have for EBM/EBP?
Industry influence…
1. Preclinical research (biotechnology and
pharmaceuticals/medical devices)
2. Phase III research
3. Phase IV research
4. Systematic reviews/guidelines
Preclinical Research
• Often conducted by PhD scientists,
sometimes MDs – generally considered to
be “basic” science (not applied)
• Traditionally, science as “search for truth”
• Now, need to be profitable:
– Decreased university budgets
– Increased expectancy that scientists fund
their own research
– Involvement of “industry partners”
Patents and Biomedical
Research
• Patents are a contract between an
inventor and society: they grant a timelimited market exclusivity (so that the
inventor can benefit from the work and
time and risk involved in inventing) in
exchange for a complete description of
an invention (so that others can
copy/improve it)
Patents
• To qualify, an invention must be:
– useful
– novel
– not obvious
Patents and Biomedical
Research
• Scientific results published in peer-reviewed
journals, so available to private industry
• Bayh-Dole Act (1980, U.S.) allows
universities and researchers to obtain
privately held patents on publicly-funded
research
– Meant to accelerate transfer of scientific
discoveries into public benefit
– Also ended up commercializing “basic”
research
Effects of commercialization of
research
• Choice of research projects - potential profit
(esp. when partnered funding occurs)
– Focus on technological solutions (drugs, devices)
rather than public health measures (prevention,
education)
• Delay in peer-reviewed publication to protect
patentable discoveries
– Effects on students
• Decrease in informal sharing of data
• Conflicts of interest…
Conflicts of interest
• Career success depends on attracting grant
funding, publication, so vested interest in
“successful” research
– Publication bias
• Researchers get consultation fees, stock options
(may be greater than academic salary)
– Members of government panels, FDA also have ties
with industry
• Increasingly, researchers are industry – they
own (or are part owners of) companies set up to
benefit from research
Ethics and research design:
Phase III trials (RCTs)
• “Gold standard” research
• Required by regulatory agencies (FDA,
Health Canada) before new drugs can be
approved
• Problems:
– “Me too” drugs
– Placebo controls
– Other tactics to achieve significant results…
The Pharmaceutical Industry
• Marcia Angell
– former editor of NEJM
– Author of The Truth About the Drug
Companies: How They Deceive Us and What
to Do About It (2004)
– CMAJ article (2004): “Excess in the
pharmaceutical industry”
Big Pharma
• Series of mergers and acquisitions -->
larger and more powerful companies
– Bristol-Myers Squibb
– Smith-Kline Beecham
– GlaxoSmithKline
Profit
• Industry is supposedly “high risk”
• But profit margins are consistently much
larger than for other Fortune 500
industries
• U.S. - price of drugs not regulated
– compare Canada - some gov’t regulation, also
partial drug coverage for seniors, inpatient
drugs covered
– U.S. highest prices paid by those with no
insurance
“Me-too” drugs
• Minor variations on already-marketed
drugs
– me-too drugs to extend monopoly
– other companies cash in on pre-existing
market
Why “me-toos” - Big Pharma
• Back-up treatment for patients who do not
respond to original version of drug
– Angell: how many back-ups do we really
need?
• Competition keeps prices lower
– Angell: No, it doesn’t.
Why “me-toos” - Angell
• Cheaper than innovative drugs and have
ready-made markets
– between 1998 and 2003, only 14% (67/148)
of drugs approved by FDA were “novel
compounds”)
• Easier than doing “real” R&D
Placebo controls
• Ethical issues re use of placebo controls in
situations when an alternative active
control already exists
• But, regulatory agencies require studies
that are placebo-controlled
– Pharmaceutical lobby? (More pharmaceutical
lobbyists in Washington than there are
members of Congress)
– “Better than nothing…”
Industry funding and positive
results
• Little external regulation of drug testing:
regulatory trials are conducted by the
company itself
• Regulatory agencies, clinicians,
researchers doing systematic reviews all
depend on integrity of these trials…
Industry funding and positive
results
• Between 2/3 and ¾ of trials published in
major medical journals are industry-funded
• Technical quality of these reports is
generally very good
• And they almost always favour the
sponsor’s drug (4x more likely to have
favourable responses in industrysponsored trials than in trials sponsored
by other sources)  publication bias?
In search of significance
• Conduct a trial of your drug against a
treatment known to be inferior
• Trial your drugs against too low a dose of
a competitor drug
• Conduct a trial of your drug against too
high a dose of a competitor drug (making
your drug seem less toxic)
In search of significance
• Conduct trials that are too small to show
differences from competitor drugs
• Use multiple endpoints in the trial and
select for publication those that give
favourable results
• Do multicentre trials and select for
publication results from centres that are
favourable
In search of significance
• Conduct subgroup analyses and select for
publication those that are favourable
• Present results that are most likely to
impress – for example, reduction in
relative rather than absolute risk
Phase IV (“postmarketing”)
studies
• In general, ~35% of a pharmaceutical
company’s budget goes to marketing
(including “medical education”) and 11
to 14% on R&D
• This 11-14% includes distributing free
samples of drugs, to interest physicians
and patients in using them.
Phase IV (“postmarketing”)
studies
• It also includes “phase IV” post-approval
studies E.g. Colazal (for ulcerative colitis)
– $500 “honorarium” to physician for starting 5
patients on the drug
– Free drugs for patients (short-term +
coupons)
– Survey at 8 weeks, including: “Overall, how
was your experience with Colazal?” (check
“extremely pleased” “pleased” “not pleased”
Phase IV (“postmarketing”)
studies
• Companies are supposed to do real
research to monitor the occurrence of
adverse effects, long-term efficacy, but
this is not enforced
• Often, warning signs are present, but
ignored:
– HRT
– Vioxx
– Paxil
Paxil (paroxetine)
• June 2004: lawsuit against manufacturer
(GSK): “repeated and persistent fraud by
misrepresenting, concealing and otherwise
failing to disclose to physicians information
in its control concerning the safety and
effectiveness of its antidepressant
medication paroxetine”
– Efficacy data had been “carefully selected” for
publication
– Downplay/disregard evidence of risks
Professional response?
• ACNP “Executive summary” by Task Force on
SSRIs and Suicidal Behavior in Youth” –
concluded that SSRIs are safe and effective for
use in children and adolescents
– 9/10 members of Task Force had consultancy and
other financial arrangements with major
pharmaceutical companies
– 3/10 were authors of paroxetine article (though they
admitted they hadn’t seen the full data)