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 researchPhase IV researchSystematic reviews/guidelines
5 Preclinical ResearchOften 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 budgetsIncreased expectancy that scientists fund their own researchInvolvement 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 PatentsTo qualify, an invention must be:usefulnovelnot obvious
8 Patents and Biomedical Research Scientific results published in peer-reviewed journals, so available to private industryBayh-Dole Act (1980, U.S.) allows universities and researchers to obtain privately held patents on publicly-funded researchMeant to accelerate transfer of scientific discoveries into public benefitAlso 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 discoveriesEffects on studentsDecrease in informal sharing of dataConflicts of interest…
10 Conflicts of interestCareer success depends on attracting grant funding, publication, so vested interest in “successful” researchPublication biasResearchers get consultation fees, stock options (may be greater than academic salary)Members of government panels, FDA also have ties with industryIncreasingly, 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” researchRequired by regulatory agencies (FDA, Health Canada) before new drugs can be approvedProblems:“Me too” drugsPlacebo controlsOther tactics to achieve significant results…
12 The Pharmaceutical Industry Marcia Angellformer editor of NEJMAuthor 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 PharmaSeries of mergers and acquisitions --> larger and more powerful companiesBristol-Myers SquibbSmith-Kline BeechamGlaxoSmithKline
14 Profit Industry is supposedly “high risk” But profit margins are consistently much larger than for other Fortune 500 industriesU.S. - price of drugs not regulatedcompare Canada - some gov’t regulation, also partial drug coverage for seniors, inpatient drugs coveredU.S. highest prices paid by those with no insurance
15 “Me-too” drugs Minor variations on already-marketed drugs me-too drugs to extend monopolyother 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 drugAngell: how many back-ups do we really need?Competition keeps prices lowerAngell: No, it doesn’t.
17 Why “me-toos” - AngellCheaper than innovative drugs and have ready-made marketsbetween 1998 and 2003, only 14% (67/148) of drugs approved by FDA were “novel compounds”)Easier than doing “real” R&D
18 Placebo controlsEthical issues re use of placebo controls in situations when an alternative active control already existsBut, regulatory agencies require studies that are placebo-controlledPharmaceutical 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 itselfRegulatory 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-fundedTechnical quality of these reports is generally very goodAnd 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 inferiorTrial your drugs against too low a dose of a competitor drugConduct 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 drugsUse multiple endpoints in the trial and select for publication those that give favourable resultsDo 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 favourablePresent 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&DThis 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 drugFree 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 enforcedOften, warning signs are present, but ignored:HRTVioxxPaxil
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 publicationDownplay/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 adolescents9/10 members of Task Force had consultancy and other financial arrangements with major pharmaceutical companies3/10 were authors of paroxetine article (though they admitted they hadn’t seen the full data)
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