1. Ethics and Research Design: Industry influences on research

3. “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?

4. Industry influence…
Preclinical research (biotechnology and pharmaceuticals/medical devices)
Phase III research
Phase IV research
Systematic reviews/guidelines

5. 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”

6. 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)

7. Patents
To qualify, an invention must be:
useful
novel
not obvious

8. 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

9. 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…

10. 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

11. 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…

12. 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”

13. Big Pharma
Series of mergers and acquisitions --> larger and more powerful companies
Bristol-Myers Squibb
Smith-Kline Beecham
GlaxoSmithKline

14. 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

15. “Me-too” drugs Minor variations on already-marketed drugs
me-too drugs to extend monopoly
other companies cash in on pre-existing market

16. 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.

17. 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

18. 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…”

19. 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…

20. 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?

21. 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)

22. 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

23. 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

24. 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.

25. 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”

26. 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

27. 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

28. 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)