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The Controversy:
Physician-Pharmaceutical
Interactions
Adam Hofmann
Senior Medical Resident, McGill University
Founder and Co-leader of No Free Lunch McGill
Statement of Disclosure
Father, CEO Mother, Former
Elder Brother,
and President Marketing
Sales Rep
Executive
Statement of Disclosure
Younger Brother
Abbie,
Pharmaceutical Dog
Introduction and Overview
Why talk about the Physician-
Pharmaceutical Relationship?
Objectives:
The Influence of Advertising
Clinical Research and the Pharmaceutical
Industry
Conclusion and Discussion
Section 1:
Pharmaceutical Advertising:
Evidence for Undue Influence?
What do we doctors think?
Attitudes: What do We Think?
Survey of Medical Students1:
Improper for Politician to Accept $500 gift:
%85
Improper for Doctors to Accept $500 gift:
%45
1- Palmisano et al., 1980
The “self-entitlement” phenomenon
2005 Update –
80% of medical students believed that
“they were entitled to gifts”
Sierles et al. JAMA 2005
Attitudes: What Do We Think?
Residents who felt that they themselves
were not influenced by pharmaceutical
advertising
61%
Number of residents who felt other
residents were also not influenced:
16%
Steinman et al, Am J Med, 2001
Pharmaceutical Advertising
A Selection of Studies to Illustrate Some
Concepts in the Literature
Research Pharmaceutical
Spending
Source: GAO-07-54
Return-On-Investment (ROI) for
various advertising methods
2005 ROI: $2.20 (GAO)
Neslin 2001, RAPP study (http://www.rxpromoroi.org/rapp/index.html)
Question 1:
Has there been any research on
the extent of the influence of
advertising on physicians?
Pharmaceutical Representatives
Pharmaceutical Representatives
Increased Pharmaceutical Representative
Contact Associated With
Increased requests for additions to hospital formulary,
compared to control doctors and competing drugs1,2
Increased prescribing cost3 (less pronounced in
academic setting vs. community setting)
Decreased prescribing of generic drugs4
Rapid awareness and prescription of new drugs5
1- Chren and Landefield, 1994 2- Lurie et al., 1990 3- Caudill et al., 1996
4- Bower and Burkitt, 1987 5- Peay and Peay, 1998
Pharmaceutical Gifts
Receiving a gift, and number of gifts received
correlated with a positive attitude toward
pharmaceutical reps, and the belief that reps do
not influence prescribing behaviour1,2.
Social Contract phenomenon
1- Hodges, 1995 2- Sandberg et al. 1997
Free Pharmaceutical Samples
Pharmaceutical Samples
Accepting samples was associated with awareness,
preference and rapid prescription of a new drug1, and
a positive attitude toward the pharmaceutical
representative2.
Inappropriate prescribing patterns found to be
correlated with number of free samples received3.
96% of physicians found to have used samples for
their own purposes in the past year4
1- Peay and Peay 1988 2- Thomson, 1994 3- Ubel et al, 2003
4- Westfall et al., 1997
Meals, Symposia, and Pharmaceutical-
Sponsored Presentations
CME and Travel Funding
Orlowski and Wateska, Chest 1992
Drug A: 81
Drug A: 272
Drug B: 34 17 months Drug B: 87
-P <0.001, both A & B
-Significantly different
pattern than nearby,
10 MDs denied any similar-sized institutions
effect of sponsored Symposium!
symposia on their
prescribing habits
Pharmaceutical-Sponsored
Presentations
Spingarn, Berlin and Strom, Acad Med 1996
22
Residents 3 Months Questionnaire:
attend; How to treat mild
53 vs. severe Lyme
controls Disease?
Pharmaceutical do not.
Speaker – a prof. of
Internal Medicine, on
Lyme Disease
Absentees more likely to Attendes were between 1.5
Attendes were more likely to 7.6 times more likely to
prescribe cost-effective, less
to prescribe choose company drug;
expensive Rx.
inappropriate Rx for
mild Lyme Disesase
Pharmaceutical-Sponsored
Presentations
Ziegler, Lew and Singer, JAMA 1995
1- 11% inaccurate
statements; all of
106 which cast the drug
statements on in a favourable
light.
drugs
collected and 2- Statements
analyzed about own drug
favourable 56% of
the time;
Pharmacists attended 15 statements about
consecutive “details” competitors – 0%
following academic rounds at
3- Only 26% of
which lunch was provided residents recalled
hearing a single
false claim.
Miscellaneous
Big Brother is Watching!
IMS Canada
“IMS HEALTH collects data from
over 65,000 sources in Canada
including … physicians…
More than 200 million transactions
are processed each year to yield
extensive information
databases of diagnosis and
treatment patterns, prescribing
Big Brother Dan patterns and pharmaceutical
utilization trends.”
Another good one: http://www.imshealthcanada.com
http://www.verispan.com/ /htmen/2_3.htm
Big Pharma is Watching!
Gonul FF et al., Journal of Marketing 2000
“(Free drug samples) might act as long-term
reminders… and dampen increased price
sensitivity…”
“prescriptions for refills tend to repeat the initially
prescribed drug…”
“detailing and samples … increase the
prescription probability of a drug…”
“Our model is flexible in offering a variety of
alternatives to pharmaceutical companies to help
determine how long and how often they
should schedule visits to physicians…”
Big Pharma is Watching
“the majority of physicians … demonstrate a lack
of price sensitivity…”
“drug manufacturers should start targeting these
physicians (a subgroup analysis) in a more
systematic way.”
Question 2:
What Impact Does the
Pharmaceutical Industry Have On
Clinical Research?
The Translation of Research into
Marketing
Case Study: Cost Effective
Medicine
Ubel et al, Journal of General Internal
Medicine 2003
1700 generalists surveyed (FP/GP, IM) on which
antihypertensive medication is:
Personal Preference
Least side effects
Most effective
Results: CCBs, ACEI > Diuretics and B-Blocker
Prescribing practices significantly
associated with free samples.
Case Study: Cost-Effective
Medicine
1700 Physicians See 1700 Patients With Hypertension…
HCTZ Amlodipine
US$0.211/month US$43.881/month
$4284.00 for $895,152.00 for
1700 pts/yr 1700 pts/yr
TOTAL SAVINGS:
$890,868
1- Mosby’s Drug Consult, 2004
Publication Bias
What is Publication Bias?
“Publication bias follows from the
selective publication of manuscripts
based on the magnitude or direction of
the study results.1”
“Positive” studies are 4 times more
likely to be published than “negative”
studies2.
In one study, 23 of 48 meta-analyses
affected3.
1- Montori et al, 2000 2- Lexchin et al., 2003 3-Sutton et al., 2000
Publication Bias:
Accusations in the Literature
Drug company support associated with
positive outcome for drug of interest1,2
Journals do not publish “negative” or
inconclusive results3,4.
1- Cho and Bero, 1996 2- Davidson, 1986 3- Dickersin et al., 1987
4- Easterbrook et al, 1994
Publication Bias:
Accusations in the Literature
Pharmaceutical companies will terminate
ongoing trials for financial reasons, even if
the scientific and societal impact is still
present1,2.
Pharmaceutical companies will employ
duplicate publication, selective publication
and selective reporting to enhance the
attractiveness of a drug3,4.
1- Evans and Pocock, 2001 2- Lievre et al., 2001 3- Huston and Moher, 1996
4- Melander et al, 2003
Publication Bias:
Accusations in the Literature
Biased Interpretations
“…conclusions of (for-profit) trials were
significantly more likely to recommend the
experimental drug… this association does not
reflect the quantitative trial results…1”
Cost-Effectiveness Analyses
Industry supports higher-cost interventions2
Pharma 8x less likely to reach unfavourable
qualitative conclusions3
1- Als-Nielsen et al., 2003 2- Azimi et al., 1998 3- Friedberg et al., 1999
Case 1: The Anti-Inflammatory
Story of the Cox-2 Inhibitors:
Lacking CLASS and VIGOR
CLASS (Celebrex, Pfizer) Trial published in
JAMA 2000 – only 6 months of 15 months
published!
VIGOR (Vioxx, Merck) Trial published in
NEJM 2000 – omitted the evidence about
major serious adverse events.
Case 1: The Anti-Inflammatory
CLASS trials* VIGOR trial
Other
Celeco ARR NNT Rofec Napro ARR NNT
NSAI RR RR
Outcome xib ARI NNH oxib xen ARI NNH
Ds 95%CI 95%CI
% % 9 mo % % % 9 mo
%
1.12 1.46
Mortality 0.48 0.43 0.58- NS NS 0.54 0.37 0.76- NS NS
2.14 2.81
0.83 0.43
Complicated
0.50 0.60 0.46- NS NS 0.40 0.92 0.24- 0.52 192
ulcers
1.5 0.78
1.22 1.28
Other serious
5.8 4.8 1.01- 1.00 100 8.4 6.5 1.10- 1.9 53
adverse events
1.47 1.50
Total 1.17 1.21
serious adver 6.8 5.8 0.99- NS NS 9.3 7.8 1.04- 1.5 67
se events 1.39 1.40
From: Therapeutics Initiative, Letter #43
Case 2: The Anti-Fungal
Johansen and Gotzsche, JAMA 1999
Meta-analysis: Fluconazole vs
Amphotericin in the context of
neutropenia.
Inappropriate comparator: Fluconazole
PO vs. Amphotericin PO
Dangerous to patients?
OR from 0.66 to 1.14 for invasive fungal
infection
Case 3: The Anti-Emetic
Tramer et al., BMJ 1997
Ondansetron in post-op emesis
9 studies, 23 publications – total of 3335
patients duplicated (28%)
No clear cross-references
NNT without adjusting for duplicates:
3.3
NNT after adjusting for duplicates:
As high as 9.5
Case 4: The Anti-Depressant
Paroxetine (Paxil, GSK) and suicidal
ideation1
1 of 3 studies published
Combined data demonstrate:
2x higher risk of suicidal ideation
No more effective than placebo
Clinical Research in SSRI use in children2:
Only 6 of 15 RCTs were published;
Upon re-analysis, SSRIs are no better than
placebo, more adverse effects
1- Marshall, 2004 2- Therapeutics Initiative, Letter #52
Just this past month…
Turner et al., NEJM 2008
“Haunted Literature”
Gotzsche 2007 PLoS Medicine
Where are we Heading?
The Good…
Integration of strict Clinical Study
Agreements in Toronto guarantees
researchers freedom to publish1.
ICMJE - clinical trial registry2
1- Naylor, 2002
2- De Angelis et al, 2004
Where are we Heading?
Contract-research organizations (CROs)
Arguably, they allow smaller biotechs to compete
% Funds to Academic Researchers1,2
1991 2000
80% 40%
1- Davidoff et al., 2001
2- Bodenheimer, 2000
Conclusions: Clinical Research
ICMJE Editors: “…the use of clinical trials
primarily for marketing, in our view, makes a
mockery of clinical investigation and is misuse
of a powerful tool.1”
“Withholding research findings is… a violation
of the fundamental goal of medical research,
which is to advance scientific knowledge in
order to cure illness and relieve suffering.2”
1- Davidoff et al., 2001
2- DuVal, 2004
Conclusion:
What is No Free Lunch McGill?
No Free Lunch McGill, based on the
international organization
www.nofreelunch.org
Mission Statement
To promote awareness and stimulate discussion
about the issues surrounding physician-
pharmaceutical interactions
