Transcript The Drug Industry and Clinicians Steven Miles, MD [email protected] Slides available Why is this ethics? I will use regimens for the benefit of the ill.

The Drug Industry and Clinicians
Steven Miles, MD
[email protected]
Slides available
Why is this ethics?
I will use regimens for
the benefit of the ill in
accordance with my
ability and my
judgment
Beneficence
Clinical Judgment
Public policy,
reimbursement,
drug approval
Hippocrates 500 BC
I do not believe that any clear
knowledge of Nature can be
obtained though any source other
Science:
Fair,and then
than a study
of medicine
transparent
only through
a thorough mastery Respecting autonomy,
acquisition
&anyone informed consent
of this science.
…Thus, if
were able
to light upon
the truth
analysis
of data
by experiment…he would always be
Any man must have the
able to make the best
personal understanding to
pronouncements of all.
I will teach them this skill and
rules and lectures and all the
rest of learning
Clinical
Education
help himself in disease and
to judge what physicians
say and what they
administer to his body
A Few Words about Conflicts of Interest
Neither the speaker nor any member of his immediate family
has any personal or institutional or financial relationship with any
health care lobbying group or insurance company or
pharmaceutical or medical device manufacturer.

I do not represent the positions of such groups on a voluntary
basis nor do I take honorariums or educational grants from such
groups.

The material for this talk was entirely compiles by independent
scholarship.

Outline
• Drug Company Sponsored Research
• Drug Marketing in Medical Education
• Consumer Marketing
Who pays for biomedical research?
$95 Billion per year.
JAMA 2005;294:1333–42.
Drug Companies’ Profits
(True/False: High drug barely cover R &D costs? FALSE)
3rd rank
Fortune Magazine
25 years of studies show corporate-sponsored research has
more pro-corporate findings than independent research.
Corporate trials
1.8 X as likely to
Corporate
favor new med/
trials 4 X as
surg /dx method
likely to be
favorable.
2003
30 studies
BMJ 2003;
326:1167-71.
2004
Multivariate
158
drugs,87
surgical, 87
other tx.
CMAJ 2004;
170:477-80.
Corporate trials
4.9 X as likely to
favor a psych med.
2005
162
multivariate RDB-PC Trials.
Am J Psych
2005; 1957-60.
Survival improved in
37% drug co trials,
17% non-company
trials (p.<04)
2006
2009
134 oncology RCTs
Cancer 2009;
115:2783-01.
See next slide.
Favorable Outcomes of Corporate Sponsored v Independent
Research Published 2000-2005 in JAMA, LANCET and NEJM
N=39, p.=07
N=205, p.002
N=104, p.001
JAMA 2006;295:2270-74.
Internal Inconsistency: Sponsored studies
CONCLUSIONS are BETTER than the RESULTS/DATA.
• 192 Randomized Controlled Trials comparing a
statin to another statin or a non statin (95/192
manufacturer funded).
• 20.2: Odds ratio of RESULTS favoring
corporate sponsor v non corporate drug (p <
0.001).
• 34.6: Odds ratio of CONCLUSIONS
favoring corporate sponsor v non corporate
drug (p < 0.001).
PLoS Medicine 2007;4(6):e184.
Cross-sectional, multivariate.
Internal Inconsistency: Sponsored studies
ABSTRACTS are BETTER than the RESULTS/DATA.
• 62% industry trials
• 0% of non-corporate trials
had a favorable outcome in the ABSTRACT that
was not supported by the DATA. (P.<.0006)
•
Amer J Opthal 2009;147:33-8. 39 studies comparing topical
prostaglandins for lowering intraocular pressure in glaucoma. 29
industry funded, 10 not. The studies were equally likely to have
data showing positive effect 24%, 20% P=1.
Corporate-sponsored COST-EFFECTIVENESS STUDIES
are more likely to be favorable.
•
Studies with industry sponsors
1.9 X more likely to have
positive conclusions about costs
than studies supported by
nonprofit organizations.
–
–
150 studies Brit J Cancer
2003;89:1405-8.
See also NEJM 1998;338:101; Brit J
Psychiatr 2003 (s)183: 498-506.
CMAJ 2007;176:199-205. 19 studies
1/1/20-7/1/06 about insurance costeffectiveness of drug-eluting stents vs
bare-metal stents.
P<.003
Delay Outcome Research and Results Publication:
Zetia and Vytorin
2002
FDA approves
with no mortality
outcome data
because it
lowered
cholesterol.
2004
2005
Makers begin
outcomes trial.
2006
April: Trial
Completed.
Tx: 800,000 Americans/week
Earn $4 Billion/yr.
20% of US cholesterol drug market.
Ad budget $155 M Zetia & Vytorin
(Generic Simvastatin
cost a third as much
and was shown to
decrease mortality.)
-Forbes
2008
Results leak:
No benefit,
Possible  Harm!
Corporate sponsored META-ANALYSES are more
likely to be favorable than independent papers.
• Corporate sponsored meta-analyses
5.1 (OR 1.5 - 16.9) times more likely to
report favorable conclusions.
– BMJ 2007;335:1202-05 124 meta-analysis, (40% supported
by a drug company), multivariate, (regression analysis)
Meta-analysis: the statistical compilation of
several studies for finding out their larger
conclusion. (Glass, 1976)
Publication Bias & Sponsored Studies
• When results are positive, sponsors more
likely to publish multiple papers on
preliminary and final results.
– BMJ 2003;326:1171-6. (42 studies)
• Duplicate publication of the same studies
resulted in meta-analyses overstating
ondansetron’s antiemetic efficacy by 23%.
– BMJ 1997;315:635-40.
Corporate Ghostwriters
• 75% in industry-sponsored trials
– JAMA 2008;299 1800-12. See also JAMA 1998;280:222-24.
• Orthopedic Devices
– Of 32 authors receiving more than $1 Million from five
orthopedic companies, 46% disclosed their support
even when writing on the company product.
– Arch Int Med 2010;Sept 13 online first.
• Refoxecoxib (Vioxx)
– 50% (36/72) of review ghost authors disclosed
support.
– JAMA 2008;299-1800-12.
Corporate Ghostwriters
• Wyeth paid Excerpta Medical (medical communications
company) $200,000 for 10 articles.
–“I was given explicit instructions about what to play up and what
to play down—whether to enhance broader off-label use of the
pain product or go strictly by the FDA.” –RS
–“I was given a list of drug company approved phrases. I was
pressured to revise my drafts to position the product more
favorably.“ –ML Lancet 1999;354:136.
• After controlling for size of benefit, sponsored papers 5.3 X
more likely to say corporate drug is “drug of choice.”
– JAMA 2003;290:921-928. 370 RCTs from a random sample of 167
Cochrane reviews.
Favorable trials are published. Negative trials are not.
Some companies present negative studies as positive.
51% of registered trials
(published and not published)
were favorable to the product.
• 94% of the registered trials that
were published were favorable.
• Publication bias increased
apparent efficacy by 32%, range
11-69% for individual drugs.
•
– N Engl J Med 2008;358: 252-60.
74 FDA-registered studies, 12
antidepressants, 12,564 patients.
See also Psych Med 2006;36: 164756.
Number of studies
Avandia – 9/2010
Sales begin.
Divided vote,
poor data on
risks. Minority
report
dissents.
1999
WHO warns about
heart effects.
GSK ordered to post unpub
trials because of corporate
suppression of data on
antidepressant suicides.
2004
2005
NEJM Meta-analysis
shows 43% 
heart attack. Extra
deaths~ 47,000. (A
peer reviewer leaked
review to Glaxo.)
FDA: Stronger label.
2006
2007
GSK internal study
(that ignores some
MIs) finds 31%
heart attack.
P=NS. GSK
conceals memo.
BMJ 2010:341:c4848.
1 Million Rxs, Sales  from
22%
$3B to $1B/Yr.
BMJ: Risks> benefits;
withdraw it. UK: Ditto.
Europe stops sales.
FDA restricts sales;
divided vote (Avandia
speakers vote).
2010
GSK to European Heart
Journal: “Withdraw this
editorial (critical of Avandia)
and refrain from publishing
it in any way.”
Sales:$500 M/Yr.
Corporate-funded authors more likely to publish
pro-corporate positions on risk controversies.
4 X more likely to
favor a controversial
diet aid (Olestra) than
those without Proctor
and Gamble funding.
P<.0001
Corporate sponsored
researchers 2.6 X more
likely to favor
controversial Calcium
channel blocker than
those without funding.
P.<.0001
1998
2000
2002
NEJM
1998;338:101-6.
2003
Am J Pub Health
2003;93:664-9.
BMJ 2002;325:249
JAMA 2000;342: 1539-44
3.4 X as likely to favor a
controversial diabetic drug
(Avandia) than those without
corporate funding. P<.0001
(Half of articles had no
disclosures of whether there
were conflicts of interest.
2005
2010
BMJ 2010;
340:c1344
doi:10.1136/bmj
.c1344
FDA Vioxx panel.
Non industry connected panelists vote 14
to 8 to keep Vioxx off market.
Panelists with company ties voted 9 to 1
to bring Vioxx back to the market.
P<.0001 {miles}
Why is this ethics?
I will use regimens for
the benefit of the ill in
accordance with my
ability and my
judgment
Beneficence
Clinical Judgment
What is your duty with
regard to reading
corporate sponsored
research?
Public policy,
reimbursement,
drug approval
Science: Fair,
transparent
acquisition &
analysis of data
Clinical
Education
Respecting autonomy,
informed consent
What is your duty to
inform a patient who
suffers a bad outcome
possibly related to
corrupted science?
Outline
• Corporate Sponsored Research
• Drug Marketing to Clinicians
• Consumer Marketing
More than half of the $1.4 billion for
accredited medical education comes
from commercial sources. BMJ 2003;326:1163
3rd Year Medical Students
• Mean exposure: 1 gift or
sponsored activity/wk.
• 93% asked or required
to attend at least 1
sponsored lunch.
• 80% believed that they
were entitled to gifts.
–
JAMA 2005;294:1034-42. Survey 1143
third-year students at 8 US medical
schools. Response rate 72.3%.
What is the effect of small drug company
gifts on Medical Students?
•
Med School A.
Favorability to
a branded statin
– Students are instructed on
Pharm sales techniques
– 53% think that drug company
materials are useful.
– 63% think they affect personal
prescribing.
•
Med School B
– 67% think drug company
materials are useful.
– 29% say they will affect
prescribing.
–
Arch Intern Med 2009;169:887-93. Small
branded items, implicit attitude test of
favorability. N1=161, 4th year students.
.05
.002
Grooming Residents for Detailing
Very appropriate
.004
.006
Very inappropriate
Acad Med 2006;81;595-602. 118 IM res
See also Acad Med 2007;82(10):S1-3; 2007;82:94-9.
Housestaff views of their own virtues
compared to their peers
•
2% of residents say rep gifts • 30% of residents say rep gifts
have a moderate to lot of
have a moderate to lot of
influence over themselves.
influence over other residents.
Am J Med 2001;110:551.
• MDs had positive views of detailing despite knowing its conflict of interest.
•To reduce cognitive dissonance they:
• avoided thinking about the conflict,
• said that interactions did not affect MDs,
J Gen Int Med 2007;22:184-90
• told how they remained impartial,
• said that meetings were educational and benefited patients. .
What Do Residents Remember
After Sales Rep’s Talk?
• 8.4 X more likely to correctly choose rep’s
product when it was the first-line agent.
• 7.8 X more likely to incorrectly choose rep’s
drug when it was a second line agent.
• No attendees, unlike those not exposed to
rep’ presentations, knew proper, cheaper drug
for the 2nd indication. (p< .05).
•
Acad Med 1996;71:86-8 (most recent data available.)
Predictors of Internal Medicine Residency Board
(ABIM) Program Pass Rates
(3 year running average)
Positively Related
• Number of faculty
Inversely Related
• Financial support
from drug
companies
• Clinical duties of
residency director
(less time for
residents)
Acad Med 2002;77:50
Free Samples & Patient Care
MDs Giving Samples
• 2.5 X as likely to start uninsured
persons on brand names rather than
generics (reverses when samples
removed).
–Southern Med J 2008;101:888-93. and Am J Med
2005;118:881-4.
• Much more willing to say drug reps
are valuable in teaching MDs about new
drugs.
–Acad Med 2009;84:994-1002.
Removing Samples
•
Shifts prescribing toward national guidelines.
• Fam Med 2002; 34:729-31. Replicated in Qual & Safety
Health Care 2007;16:266-70.
• Results 1 to 15%  generic prescribing, p>.001.
• Arch Intern Med. 2009;169(13):1241-2.
1 clinic pre and post ending samples. First
line tx by Joint Nat Comm Tx HBP.
Are Drug Ads’ Claims in Medical Journals Supported?
Psychiatry Journal Ads
•
53% of efficacy claims supported
by cite.
•
Authors asked companies for
data supporting claims for which
ad did not give data.
–
2 of 9 companies supplied data.
–
6 of 9 did not respond.
–
Wyeth: “Unfortunately our internal
policies do not allow for
distributions of unpublished data.”
• J Nerv Ment Dis 2008;196:26773. 69 unique ads in Arch Gen
Psych, Am J Psych, NEJM, JAMA,
2006.
Rheumatology Journal Ads
18% of 300 cites support claims.
• 49% of cited randomized
controlled trials supported claim.
•
– 97% of RCTs funded by drug co.
17% of claims were supported.
• 13% of ads were not supported
by cited study.
•
• Rheumatology 2006;45:11154-7.
84 unique ads in Arth and Rheum,
Rheumatology, Seminar in Arth
and Rhem, J Rheum.
Drug Rep Dinner Course and Prescribing
Relative Sales
Invitation
Course
Chest
1992;102:270-3.
I use this old paper
because it is the
only such study.
Months
Off-label Marketing at Conferences & Offices
Neurontin-2003
• Pfizer paid academic MDs $1,000 to
$300,000/year to promote non-FDA
uses.
– 38% of sales visits to MDs: main
message promoted off label use.
• PLoS 2007;40743-50. Trial evidence.
• ‘This fraudulent promotion corrupted the
information relied upon by doctors thereby
putting patients at risk.‘ Fed Prosecutor.
• 2003
– Neurontin sales $2.7 Billion.
– 90% of Rx for off label use.
– Pfizer guilty of illegal marketing; paid
$430 M.
– NYT 5/30/03 C1,2; NYT 5/14/04 C1.
Bextra, Geodon, Zyvox,
Lyrica 2009
• Department of Justice: Pfizer
– promoted Bextra for several uses and
dosages that the FDA specifically declined
to approve because of safety concerns.
– improperly promoted the anti-psychotic
Geodon, the antibiotic Zyvox and the anticonvulsant Lyrica.
• Pfizer pay $1.3 billion in criminal fines
and $1 billion in civil fines.
• Note: Pfizer pulled Bextra from the market in
2005 because FDA concluded its risks, including
a rare but serious skin reaction, outweighed its
benefit.
Ethics and Drug Marketing to Clinicians
Public policy,
reimbursement,
drug approval
Beneficence
Clinical Judgment
I will teach them this skill
and rules and lectures
and all the rest of
learning
Science: Fair,
transparent
acquisition &
analysis of data
Clinical
Education
Respecting autonomy,
informed consent
What is your duty to
address the effects of
sales representatives on
clinicians and medical
trainees?
Outline
• Corporate Sponsored Research
• Drug Marketing to Clinicians
• Consumer Marketing
Ads’ Effects on Patients
• Patients with more self-reported ad exposure,
conditions treatable by advertised drugs, or more
reliant on advertising ask for more advertised
drugs.
• 6% of patients request an advertised drug.
• Pts asking for advertised drug are 17 times as
likely to get it.
• MDs are more ambivalent about value of a
requested advertised drug.
•
BMJ 2002; 324: 278-9. 2 sites, 78 MDs, 1431 patients.
See also: JAMA 2005;293:1995-02.
Vioxx
Merck documents obtained at trial
show that it edited out data on
excess deaths in 2001.
– JAMA 2008;299:1813-17.
Meta-analysis (4 studies, N=18,000): risk  X
2.4 heart attack, unstable angina, sudden
cardiac death, stroke, TIA with COX-2 inhibitors.
JAMA 2001;286:954-59.
September 2004: Merck withdraws Vioxx
because a new study (N=2,600) shows  risk of
heart attack and stroke. Merck stock drops 27%,
erasing $25 B of market value.
Vioxx caused ~ 50,000 excess deaths.
Some Ad Campaigns Seem Made to Keep
Demand From Softening During A Price Hike
12%
price
hike
Arch Int Med 2009;169:1694-74. Clopidogrel (Plavix) data refers to Medicaid dose
charges. Growth in use continued up at same rate through price increase. This is
Medicaid’s 10th most costly drug ($400 M in 2003). Total sales in 2005 were $5.9 B.
Evening News and Prime Time Drug Ads
• 95%: Emotional appeals
• 82%: Factual claims.
• 86%: Rational arguments.
• 58%: Framed med need in terms of
losing control over an aspect of life.
• 85%: Framed med as regaining
control over life.
• 78%: Showed med use as
engendering social approval.
• 58%: Portrayed product as a
medical breakthrough.
• Ann Fam Med 2007;5:6-13.
Why are Drug Ads a Matter for Medical Ethics?
Public policy,
reimbursement,
drug approval
Beneficence
Clinical Judgment
Science: Fair,
transparent
acquisition &
analysis of data
Clinical
Education
Respecting autonomy,
informed consent
Any man must have the
personal understanding to
help himself in disease and
to judge what physicians
say and what they
administer to his body
Steven Miles, MD
Slides Available
[email protected]