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

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
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
Funding for Medical Research
35
30
$ Billions
25
NIH
20
Industry
(domestic)
15
10
5
0
1995
1997
1999
2001
2003
2005
Funding for Clinical Research,
United States, 2002
Billions
$1.10
$0.56
Biopharma
Device makers
NIH
$3.90
CenterWatch 2003
Fewer Non-Industry Funded
Trials in the UK
Chalmers et al. BMJ 2003;
327:1017-20
Health R&D in Canada, 2004
0.79
1.10
0.46
0.36
Federal
government
Provincial
government
Business enterprise
Higher education
1.49
Spending in billions of dollars,
total $5.75 billion
1.56
Private non-profit
Foreign
Statistics Canada. Science Statistics. Catalogue 88-001-XIE
Clinical R&D Spending in
Canada, 2004
Spending in billions
6
5.75
5
4
3
2
0.682
1
0.67
0
Total R&D
Industry
financed clinical
R&D
Total CIHR
budget
The Willie Sutton Rule
Why did he rob
banks?
“That’s where the
money is”
Source of Support and Choice
of Research Topic
Industry support
Choice of research
topic influenced by
commercial
application
No industry
support
1985
(%)
1994/5
(%)
1985
(%)
1994/5
(%)
30
35
7
14
Blumenthal et al. Science 1986;232:1361-6
Blumenthal et al. NEJM 1996;335:1734-9
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
Tallon et al. Lancet 2000;355:2037-40
128
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
Outcome of Industry Funded
Research
Odds ratio meta-analysis plot (fixed effects)
Azimi et al (15)
Cho et al (17)
Clifford et al (18)
Davidson (19)
Dieppe et al (21)
Djulbegovic et al (22)
Djulbegovic et al (23)
Friedb erg et al (26)*
Friedb erg et al (26)**
Kamal-Bahl et al (29)#
Kamal-Bahl et al (29)##
O.R. 4.09
Koep et al (33)
Mandelkern (35)
Sacristan et al (39)^
Sacristan et al (39)^^
Lexchin et al.
BMJ 2003;326:116770
Thomas et al (41)
Vandenb roucke et al (42)
Yaphe et al (44)
0.1 0.2
0.5
1
2
5
10
100
1000
MH pooled odds ratio = 4.051419 (95% CI = 2.978525 to 5.510779)
1.00E+05
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 2003;290:921-8
Outcome of Industry Funded
Research - III
• Moncrieff. Br J Psych 2003;163:161-6
– Industry funded clinical trials on clozapine showed greater positive
effect than trials with other sources of funding
• Baker et al. Br J Psych 2003;183:498-506
– Pharmacoeconomic studies of antidepressants revealed clear
associations of study sponsorship with quantitative outcome
• Bhandari et al. CMAJ 2004;170:477-80
– 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)
Outcome of Industry Funded
Research - IV
• Montgomery et al. Controlled Clinical Trials
2004;25:598-612
– Industry funded studies significantly favoured second generation
over first generation antipsychotics compared to non-industry
funded studies
• Heres et al. Am J Psychiatry 2006;163:185-94
– 33/42 head-to-head trials of second generation antipsychotics
funded by industry
– 90% of these reported overall outcome favoured sponsor’s 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)
Outcome of Industry Funded
Research - V
• Ridker et al. JAMA 2006;295:2270-5
– 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% forprofit funding (p for trend 0.002)
• Perlis et al. Journal of the American Academy of
Dermatology 2005;52:967-71
– 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)
Outcome of Industry Funded
Research - VI
• Perlis et al. American Journal of Psychiatry
2005;162:1957-60
– 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 (p<0.001) and among
industry-supported studies (p<0.001)
• Barden et al. Pain 2006;121:207-18
– 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
Outcome of Industry Funded
Research - VII
• Procyshyn et al. Can J Psych 2004;49:601-606
– 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 2006;333:782
– Industry supported meta-analyses less transparent, fewer reservations
about methodological limitations of included trials and more favourable
conclusions than corresponding Cochrane reviews
Research Results and
Funding
Type of
research
Clinical trials
Pharmacoeconomic
studies
Meta-analyses
Results
favour
industry
10
Results do
not favour
industry
1
3
0
1
0
“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
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 2004;170:489-91
JAMA 2001;286:2398
Ghostwriting - Articles on
Paroxetine
Source of article
Medline listing
per author
Literature profile
per article
Citation rate of
series
Current Medical
Directions
(Ghostwritten)
Other
(Not ghostwritten)
70
37
1839
283
20.2
7.7
Healy et al. British Journal of Psychiatry 2003;183:22-7
Conflict of Interest and Calcium
Channel Blockers
100% 96%
90%
80%
70%
60%
60%
50%
40%
37%
30%
20%
10%
0%
Supportive
authors
Neutral
authors
Critical
authors
Stelfox NEJM 1998;338:101-6
Conclusions of authors
about value of calcium
channel blockers as a
function of financial
relationship with
company making
product (p value for trend
<0.001)
Declaration of Conflict of
Interest
90
Percent of studies
80
70
60
50
Drug treatment studies
with COI
Drug treatment studies
no COI
40
30
20
10
0
Positive
Mixed
Negative
Friedman, JGIM 2004;19:51-6
Other
Declaration of Conflict of
Interest
Higher the score, the
more strongly the
treatment is
recommended
Kjaergard et al. BMJ 2002;
325:249
CPGs and Conflict-of-Interest
JAMA 2002;287:
612-7
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 2005;437:1070-1
Lilly and Xigris
NEJM 2006;355:1640-2
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
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
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
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 editorial…the
publication of your editorial would, in fact, not be
accepted in some quarters…and apparently went
beyond what our marketing department was willing to
accommodate”
Dyer. BMJ 2004;328:244
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 1992;116:912-9
What Happened to Ad
Revenue?
50
45
40
35
30
25
20
15
10
5
0
Ann Int Med
Arch Int Med
JAMA
AJM
NEJM
Percent decrease in volume of drug ads in
period 7/92-12/94 (compared 1/91-6/92)
Landefeld et al: JGIM 1995;10(Suppl):111
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 2003;361:10
Changes in Prescribing for
Hypertension
Drug class
1985
1995
Percent of
Daily
Percent of
Daily
respondents ingredient respondents ingredient
cost ($)
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 1999;161:699-704
Prescribing of Some New
Products is Additive Not
Replacement
Total NSAID
prescribing
increased
when
COXIBs came
on the market
ICES, Nov. 2003
The Result: More GI Bleeds
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