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 time-limited 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 industry-sponsored 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)