Whose Evidence, What Kind of Practice: Profits, Research and Medical Practice

1
Whose Evidence, What Kind of Practice Profits,
Research and Medical Practice

• Joel Lexchin MD
• School of Health Policy and Management
• York University
• Emergency Department
• University Health Network

2
Outline

• Who is spending money
• Funding and choice of research topic
• Funding and outcome of research
• Suppressing biasing research results
• Conflict-of-interest
• Research results
• Clinical Practice Guidelines
• Money and medical journals
• Prescribing behaviour

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Funding for Medical Research
4
Funding for Clinical Research, United States, 2002
Billions
CenterWatch 2003
5
Fewer Non-Industry Funded Trials in the UK
Chalmers et al. BMJ 2003 3271017-20
6
Health RD in Canada, 2004
Spending in billions of dollars, total 5.75
billion
Statistics Canada. Science Statistics. Catalogue
88-001-XIE
7
Clinical RD Spending in Canada, 2004
8
The Willie Sutton Rule

• Why did he rob
• banks?
• Thats where the
• money is

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Source of Support and Choice of Research Topic
Industry support Industry support No industry support No industry support
1985 () 1994/5 () 1985 () 1994/5 ()
Choice of research topic influenced by commercial application 30 35 7 14
Blumenthal et al. Science 19862321361-6 Blumenth
al et al. NEJM 19963351734-9
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Drug Companies Directing Research OA of the Knee
Treatment Commercially sponsored (number)
Alternative complementary 5
Drug (injected) 5
Drug (oral) 109
Education 1
Physiotherapy exercise 3
Surgery 5
Total 128
Tallon et al. Lancet 20003552037-40
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Drug Companies Directing Research OA of the Knee

• Rheumatologist Focus Group
• NSAIDs over-researched especially through
  commercial sponsored drug trials
• Patient Focus Group
• Favoured conservative treatments such as
  physiotherapy
• More research on education and self-help
• GP Focus Group
• Research on surgical success rates and
  conservative treatments
• Oral drugs over-researched
• Physiotherapist Focus Group
• Absence of research on physiotherapy exercise
• Dominance of drug trials

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Outcome of Industry Funded Research
O.R. 4.09
Lexchin et al. BMJ 20033261167- 70
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Outcome of Industry Funded Research - II

• 370 drug trials from 25 Cochrane reviews
• Trials funded by for-profit organizations
  significantly more likely to recommend
  experimental drug as treatment of choice compared
  to trials funded by nonprofit organizations OR
  5.3 (95 CI 2.0, 14.4) (After adjusting for
  treatment effect and double blinding)
• Als-Nielsen et al. JAMA 2003290921-8

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Outcome of Industry Funded Research - III

• Moncrieff. Br J Psych 2003163161-6
• Industry funded clinical trials on clozapine
  showed greater positive effect than trials with
  other sources of funding
• Baker et al. Br J Psych 2003183498-506
• Pharmacoeconomic studies of antidepressants
  revealed clear associations of study sponsorship
  with quantitative outcome
• Bhandari et al. CMAJ 2004170477-80
• 158 RCTs of drug products from 5 high-impact
  general medical journals
• Industry trials more likely to be favourable to
  product OR 1.6 (95 CI 1.1, 2.8)

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Outcome of Industry Funded Research - IV

• Montgomery et al. Controlled Clinical Trials
  200425598-612
• Industry funded studies significantly favoured
  second generation over first generation
  antipsychotics compared to non-industry funded
  studies
• Heres et al. Am J Psychiatry 2006163185-94
• 33/42 head-to-head trials of second generation
  antipsychotics funded by industry
• 90 of these reported overall outcome favoured
  sponsors drug
• Same drugs compared but with different sponsors
  had contradictory results
• Bell et al. BMJ 2006 on-line 31 March 2006
• 494 studies measuring health effects in QALYs
  published up to December 2003
• Cost effectiveness studies funded by industry
  more likely to report rates favourable ratios
  (below 20,000, 50,000 and 100,000)

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Outcome of Industry Funded Research - V

• Ridker et al. JAMA 20062952270-5
• 324 superiority trials of cardiovascular medicine
  published between Jan. 1, 2000 and July 30, 2005
  in JAMA, Lancet and NEJM
• 205 trials on drugs proportions favouring newer
  treatments were 39.5 not-for-profit funding,
  54.4 jointly funded and 65.5 for-profit funding
  (p for trend 0.002)
• Perlis et al. Journal of the American Academy of
  Dermatology 200552967-71
• 179 RCTs in dermatology published between Oct. 1,
  2000 and Oct. 1, 2003
• Industry funded studies more likely to report
  positive findings (65 vs. 35, p 0.001)

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Outcome of Industry Funded Research - VI

• Perlis et al. American Journal of Psychiatry
  20051621957-60
• 162 double-blinded placebo-controlled RCTs
  published between 2001 and 2003
• Industry support not associated with positive
  outcome but if one or more authors had potential
  conflict of interest there was a significant
  association with positive trial outcomes among
  all studies regardless of funding source
  (plt0.001) and among industry-supported studies
  (plt0.001)
• Barden et al. Pain 2006121207-18
• Examined industry funded analgesic trials where
  same drug was test and comparator
• Except for one case (sumatriptan headache
  response at 2 h) no difference in pain relief
  when drug was test or comparator

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Outcome of Industry Funded Research - VII

• Procyshyn et al. Can J Psych 200449601-606
• 372 clinical trials on 3 atypical antipsychotics
  124 industry sponsored
• No industry sponsored trial reported negative
  results (findings favouring comparator serious
  concerns about safety or efficacy recommended
  comparator)
• Jorgensen et al. BMJ 2006333782
• Industry supported meta-analyses less
  transparent, fewer reservations about
  methodological limitations of included trials and
  more favourable conclusions than corresponding
  Cochrane reviews

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Research Results and Funding
Type of research Results favour industry Results do not favour industry
Clinical trials 10 1
Pharmaco-economic studies 3 0
Meta-analyses 1 0
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Study 329 showed trends in efficacy
The second study failed demonstrate any
separation of Seroxat/Paxil from placebo
Data from these 2 studies will therefore not be
submitted to the regulatory authorities
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And GSK Gagged Researchers

• Those researchers, including myself, who did see
• results of negative paroxetine industry trials
  were
• prohibited by nondisclosure contracts from
• discussing them.
• Jane Garland MD
• Pediatric Psychiatrist
• Vancouver
• Garland. CMAJ 2004170489-91

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JAMA 20012862398
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Ghostwriting - Articles on Paroxetine
Source of article Source of article
Current Medical Directions (Ghostwritten) Other (Not ghostwritten)
Medline listing per author 70 37
Literature profile per article 1839 283
Citation rate of series 20.2 7.7
Healy et al. British Journal of Psychiatry
200318322-7
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Conflict of Interest and Calcium Channel Blockers

• Conclusions of authors
• about value of calcium
• channel blockers as a
• function of financial
• relationship with
• company making
• product (p value for trend
• lt0.001)

Stelfox NEJM 1998338101-6
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Declaration of Conflict of Interest
Friedman, JGIM 20041951-6
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Declaration of Conflict of Interest
Higher the score, the more strongly the
treatment is recommended
Kjaergard et al. BMJ 2002 325249
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CPGs and Conflict-of-Interest
JAMA 2002287 612-7
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Conflicts of Interest in Clinical Practice
Guidelines
Over 200 guidelines examined only 90 contained
details about individual conflicts of interest
of those only 31 free of industry influence
Nature 20054371070-1
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Lilly and Xigris
NEJM 20063551640-2
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Lilly and Xigris

• 2002 - Lilly hires Belsito Co. to improve sales
  of Xigris
• Part of campaign focused on drug being rationed
  because of expense and doctors systematically
  forced to decide who would live and die
• Lilly provided group of doctors and bioethicists
  with 1.8 million grant to address ethical issues
  raised by rationing in ICU setting

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Lilly and Xigris

• Surviving Sepsis Campaign
• Lilly provided 90 of funding for creation
  publication of guidelines around sepsis
  management
• Guidelines give highest grade to therapies
  subject to RCTs - therefore Xigris got very
  favourable rating (grade B) because of PROWESS
  study whereas antibiotics, fluids, vasopressors
  received lower ratings (grades D or E) because
  had not undergone RCTs owing to lack of equipose

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Lilly and Xigris

• PROWESS showed increased risk serious bleeding
  with Xigris
• Two further studies (ADDRESS and RESOLVE)
  terminated early because unlikely to show benefit
  confirmed bleeding risk
• No mention of ADDRESS study in guidelines
• ENHANCE study indicated bleeding risk might be
  greater than originally estimated
• Guidelines included data from ENHANCE but
  possible magnitude of increased risk not noted
• Guidelines do not note that Infectious Disease
  Society of America declined to endorse them

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Reluctance to Run Critical Articles

• Transplantation and Dialysis rejected editorial
  questioning value of epoetin in end-stage renal
  disease
• Letter from editor to author
• I have been over-ruled by our marketing
  department with regard to publishing your
  editorialthe publication of your editorial
  would, in fact, not be accepted in some
  quartersand apparently went beyond what our
  marketing department was willing to accommodate
• Dyer. BMJ 2004328244

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Does Ad Revenue Bias Journal Content?

• Annuals of Internal Medicine, June 1992
• Article analyzing 102 journal advertisements from
  10 leading medical journals
• Expert reviewers
• 44 ads lead to improper prescribing
• 34 ads needed major revisions
• 28 ads should not have been published
• Wilkes et al. Ann Intern Med 1992116912-9

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What Happened to Ad Revenue?
Landefeld et al JGIM 199510(Suppl)111
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Why Did This Happen?

• Robert Fletcher (co-editor of Annals)
• The episode revealed the true colours of the
• pharmaceutical industry, which was willing to
• flex its considerable muscles when it felt its
• interests were threatened.
• Fletcher. Lancet 200336110

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Changes in Prescribing for Hypertension
Drug class 1985 1985 1995 1995
Drug class Percent of respondents Daily ingredient cost () Percent of respondents Daily ingredient cost ()
ACE 5.2 1.03 25.4 0.91
Beta-blocker 21.9 0.62 22.1 0.68
CCB 2.1 1.07 19.7 1.24
Diuretic 31.3 0.05 17.2 0.10
Combination or other 39.6 0.63 15.6 1.32
Wolf et al. CMAJ 1999161699-704
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Prescribing of Some New Products is Additive Not
Replacement
Total NSAID prescribing increased when COXIBs
came on the market
ICES, Nov. 2003
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The Result More GI Bleeds
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Conclusion

• Follow the money
• Different funders have different interests
• Those interests determine
• What kind of research gets done
• What kinds of bias might be present
• What the outcomes are
• How those outcomes are reported
• Ultimately how doctors prescribe
• Right now the pharmaceutical industry has the
  money