Transcript Drug Lords - University of Minnesota

The Drug Industry and Clinicians
Steven Miles, MD
[email protected]
Slides available
Prescription Costs & Inflation
 Declining inflation due to:
-  Medicaid
-  new drugs
-  generics.
Annual Inflation
20%
15%
Rx in total
US Health
Costs
Hospital
Clinical
Service
Prscfb'd
Rx
10%
5%
CPI
$200 B
0%
Hosp
Kaiser Family Foundation
Clin Svcs
Rx
Other
2000 2003 2005
Why did Drug Expenditures Increase
from 1994-2005?
Increased
cost of
drugs
Shift to
more
expensive
drugs
Kaiser Family Foundation
# of Rx/ person
 from 7.9 to 12.4
Increased
number of
Rxs
Median Return on Revenue
(or “the myth that drug prices reflect R &D costs and risks”)
Drug sector
Median indust
20%
2th
15%
10%
5%
19
94
19
96
19
98
20
00
20
02
20
05
20
07
0%
Fortune Magazine
Drug Company Political Spending
Federal Campaign Donations
$ Millions
Federal Lobbying
$ Million
From Indiv
$160
From Pacs
% to Repubs
$20
80%
70%
$120
$15
60%
$80
50%
$10
$40
40%
30%
$5
$0
2003-4
20%
10%
2005-6
$0
1100 Pharmaceutical lobbyists
(100 Senators)
(476 Congressmen)
Center for Public Integrity
0%
1992
1996
2000
2004
Center for Responsive
Politics/ OpenSecrets.org
Political Priority: Extend patents
• 1984: US law extends Rx patents 5 years to allow for
R & D time.
• 1994: GATT extends drug patents 22 months more.
• 1999 Inventors Protection Act
• Overall Patents increased 8.1 to 15 years with longer
increases for more recent drugs despite faster FDA
approval.
– National Institute for Health Care Management,2002
Best Pharmaceuticals for Children Act 2002
• Extends 188 patents for six months if maker
agrees to meet FDA requirement that new
drug applications are studied in relevant
pediatric groups.
• Pediatric tests: $3.87 M /drug.
• FDA: patent extensions worth 40 times that.
Coalition for Children s Health, "leading coalition in Washington on
children s health policy," is funded by drug industry and chaired by
ex drug lobbyist. It is now closed.
• 3 of 4 sponsors in top recipients of drug campaign gifts.
• Subcommittee members voting “Aye” received $64,691 since 1990;
“Nays” $25,493.
•
Medicare Prescription Drug and Modernization Act 2003
Medicaid may not mandate
bulk purchasing (has
lowered drug prices).
• Medicare is not direct
purchaser (no price controls)
and cannot press for
discounts.
• No fed funds for drug costeffectiveness studies.
• Medicare may not interfere
“in any way with
negotiations” between
insurers and drug corps.
•
•
•
$50 million in TV ads
$10 million to Chamber of
Commerce to run pro drug
position ads.
“Having both house of Congress
Republican-controlled was great.
Like in Monopoly, when you get to
add hotels.”
Drug lobbyist.
NYT 9/5/2003 A1, C4
FDA Drug Approvals
FDA Approvals 2000-04
New Drug
New Combo
37
Modified
Nothing new
33
120
Months to approval
35
30
25
20
15
10
5
0
1986
1990
1994
1998
2000
New Drug Approval Times in Months
237
http://www.fda.gov/cder/reports/reviewtimes/
default.htm#FDA%20Review
Lawsuits to Delay Generics
• Generic prices will be 80% lower.
• Claritin’s lawsuit to delay generics by six
months cost $5 Million.
• Claritin 6 month sales: $1.3 Billion.
– NYT 3/11/2001
Who pays for drug research?
Non NIH
Federal, 8
2005 $ Billion
Industry, 51.3
NIH, 28.6
Foundations,
2
Univ, 6.5
State/Loc
Gov, 2.4
Drug Industry Research
18% basic research
for breakthrough
drugs
• 82% derivative
innovations & testing
on existing drugs.
Nat Sci Found 2003.
•
Publication Bias & Sponsored Studies
• Sponsored studies:
– 4 X more likely to be favorable.
(30 studies) BMJ
2003;326:1167-71.
– 1.8 X more likely to favor new industry
med or surg tx. (multivariate analysis of 158 drug, 87 surgical,
87 trials of other tx, 1/99-6/01, 13 leading journals. 122 declared industry
funding). CMAJ 2004;170:477-80.
Profit v not For Profit CV Research
in JAMA, LANCET and NEJM 2000-2005
% of Studies Favoring Technology
Not for Profit
Corporate
100
80
60
N= 39, P= .07
N = 104, P =.001
N= 205, P=.002.
40
20
0
Drugs
Devices
JAMA 2006;295:2270-74.
Other: eg. Lab tests
RCTs comparing a statin drug to
another statin or non-statin drug
• 50% 95/192 of RCTs were funded by industry
•20.2: Odds ratio of results favoring corporate
sponsor v non corporate drug [CI 4.4-93], p <
0.001).
•34.6: Odds ratio of conclusions favoring
corporate sponsor v non corporate drug [CI 7.1168], p < 0.001).
PLoS Medicine 2007;4(6):e184.
Cross-sectional, multivariate.
Profit v Not For Profit Cost-Benefit Studies
•
Studies with industry sponsors
1.9 X more likely have positive
conclusions about costs than
studies supported by nonprofit
organizations.
–
–
150 studies Brit J Cancer
2003;89:1405-8.
NEJM 1998;338:101; Brit J Psychiatr
2003 (s)183: 498-506; Pharmacoeconomics 1997;11:289-91.
2007: FDA allows 5 experts with
conflicts of interest to serve on its
Committee evaluating Medtronic’s new
drug-eluting stent. 3 waivers, including
the chair, have Medtronic relationships.
Cor Stent Cost Benefit Studies
Favor wide use
Do not favor
15
10
P=.003
5
0
Corp Spon
Non Corp
Spon
CMAJ 2007;176:199-205. 19 studies
1/1/20-7/1/06 about insurance costeffectiveness of drug-eluting stents vs
bare-metal stents.
Publication Bias & Sponsored Studies
• Duplicate publication of the same
studies resulted in meta-analyses
overstating ondansetron’s antiemetic
efficacy by 23%.
–
BMJ 1997;315:635-40.
• When results are positive, sponsors
more likely to publish multiple papers
on preliminary and final results.
–
BMJ 2003;326:1171-6. (42 studies)
Drug Company Meta-Analysis
• Of 124 meta-analysis,
– 40% were supported by a drug company.
– Corporate sponsored were 5.1 (OR 1.5 16.9) times more likely to report favorable
conclusions.
• BMJ 2007;335:1202-05 (regression analysis)
Meta-analysis: the statistical compilation of
several studies for finding out their larger
conclusion. (Glass, 1976)
Corporate Ghostwriters
• 75% in industry-sponsored trials
• JAMA 2008;299 1800-12
• 11-16% of papers
• JAMA 1998;280:222-24.
• See also JAMA 1994;271:469-71.
• Refoxecoxib (Vioxx)
– 92% of clinical trials ghost authors
disclosed industry support.
– 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
are 5.3 X more likely to recommend experimental
drug as “drug of choice.” JAMA 2003;290:921-928 370 RCTs
from a random sample of 167 Cochrane reviews.
Non-Dissemination-12 Antidepressants
Number of studies
•
Publication record:
– 94% of trials were positive
•
Truth:
– 51% of trials were positive.
•
Meta-analyses: publication
bias increased apparent
efficacy by 32% for all 12
drugs, range 11-69% for
individual drugs.
– N Engl J Med 2008;358:
252-60. 74 FDA-registered
studies, 12,564 patients.
40
30
20
10
0
Positive
Studies
Misleadingly Positive Publication
Not Published
Published
See also Psych Med 2006;36:1647-56.
Negative
Studies
Corporate Non-Dissemination
• Terminating study in progress that
– Doesn’t favor the sponsor. Lancet 1987 5/9/87 p 1091
– No longer serve a marketing priority because of new drug
entering market.
BMJ;2001;322:603-6
• Threatening to end relationships with researchers
who do not deliver favorable findings.
• Threaten to sue researchers or journals if
unfavorable, albeit accurate, data is published.
– NEJM 1998;338:101; 2000;342:1539-44 JAMA. 1999:1453-7
Delay Outcome Research and Results Publication:
Zetia and Vytorin
• Tx: 800,000 Americans/week
• Earn $4 billion/yr.
– Generic ZoCor costs a third as much.
• 20% of US anti- cholesterol drug market.
2008
2002
2004
2006
FDA approval
Makers begin
events trial.
April: Trial
Completed.
Results leak:
No benefit
Possible  Harm.
• 2005:Ad budget $155 Million Zetia and Vytorin -Forbes
Relationships between Authors of Clinical
Practice Guidelines and Pharmaceutical Industry
•
•
Researchers accepting sponsor funds
•
•2.6 x as likely to favor a controversial
Ca++ channel blocker than those
without funding. P.<.0001
•
•NEJM 1998;338:101-6.
•4 x as likely to favor a controversial
diet aid (Olestra) than those without
Proctor and Gamble funding. P<.0001 •
•Am J Pub Health 2003;93:664-9.
•See also BMJ 2002;325:249;
JAMA 2000;342:1539-44
Votes on FDA Vioxx panel.
Non industry connected
panelists voted 14 to 8 to
keep Vioxx off the market.
Panelists with company
ties voted 9 to 1 to bring
Vioxx back to the market.
P<.0001 {miles}
PR and Medical Education
• Omnicom, Interpublic, and WPP (Madison Avenue’s 3
largest PR firms) have spent $10s of millions buying
companies to perform drug clinical trials.
“We provide services that go
• The PR companies
from the beginning of drug
– Write clinical papers
development all the way to
– Offer CME
the launch of your product.”
– Recruit peer MDs to promote drugs. CEO
• NYT 9/22/02 C1,4
• 42% of news reports of corporate drug studies
disclose funding; 67% refer to drug by brand name.
– JAMA 2008;300:1544-50.
Journals Strike Back: 9/2001
•
Reserve right to refuse
corporate sponsored studies
unless researchers are
guaranteed independence.
–
–
–
–
•
New England J Med
Lancet
Annals of Inter Med
JAMA
Ann Int Med 2001;135:463-5.
• “patently absurd…
The journals are
becoming more and
more antithetical to
even considering an
industry
perspective.”
– Senior VP, PhRMA
Drug Detailing, Vermont 2006
Cash
Food
Other
• 81 drug makers
• Spent $2.47 M on
honoraria,
consulting fees,
travel expenses, etc
Excludes:
on physicians,
•Advertising,
•Salaries of detailers,
hospitals,
•Free samples,
•Compensation for clinical trials,
universities etc.
•Payments under $25,
•Some educational scholarships
• 90% to prescribers
• Attorney General
Vermont 2007
•Unrestricted continuing medical education
grants.
American Psychiatric Assn
• Pharmaceutical Revenue
– 28% ($14 M) of 38,000 member org
budget.
• Amednews.com 2008 Aug 18.
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.
100%
80%
60%
40%
20%
0%
JAMA 2005;294:1034-42. Survey 1143
third-year students at 8 US med
schools. Response rate 72.3%.
Most drug co' Grand OK to accept
Rounds are helpful
gifts/lunches
& educational. because they have
little influence.
Co' material
educational.
Grooming Residents for Detailing
Lunch
4
Talk @ Noon
Very appropriate
.004
3
.006
2
1
Very inappropriate
PG1
PG2
PG3
Acad Med 2006;81;595-602. 118 IM res
See also Acad Med 2007;82(10):S1-3; 2007;82:94-9.
Comparing Physicians’ and Patients’ Attitudes
Toward Drug Industry Gifts
Percentage that considered gift influential
60
Patients
Physicians
50
40
P<0.0001 for all
30
20
10
0
Pen
Lunch
Dinner
Half of pts knew of such gifts. Of those unaware, 24%
said this diminished their perception of MDs.
J Gen Int Med 1998;13:151
Housestaff views of their own virtues
compared to their peers
•
2% of residents say rep
gifts have a moderate to
lot of influence over
themselves.
•
30% of residents say rep gifts
have a moderate to lot of
influence over other residents.
• 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,
• told how they remained impartial,
• said that meetings were educational
and benefited patients.
J Gen Int Med 2007;22:184-90.
(RN students similar Nurse Ed
Today 2007;27:551-60)
Am J Med 2001;110:551.
Sales Reps’ Information
• 11% of statements were inaccurate; all errors
favored promoted drug.
• No statements about competitors' were favorable,
but all were accurate.
• 37% of attendees said rep info influenced
prescribing.
•One University teaching hospital.
•JAMA 1995;273:1296-8.
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).
Academic Medicine. 1996;71:86-8
Drug Rep Course and Prescribing
7
Relative units
6
Invitation
5
4
Hosp A
Nation
3
Course
2
1
0
1
4
7
10
13
16
19
22
25
28
31
Months
Chest 1992;102:270-73
Off-Label Marketing: Neurontin
•
Pfizer paid academic MDs
$1,000 to $300,000/year
to promote non-FDA
approved uses.
•
Corporate notes (obtained
at trial)
– 65% of MDs valued sales
rep’ info.
– 38% of visits: main
message promoted off
label use.
•
‘This illegal and fraudulent
promotion corrupted the
information relied up by doctors
in their decisions thereby
putting patients at risk.‘
•
5/04/03 Pfizer pled guilty to
illegally marketing; paid $430 M
from set aside funds.
• PLoS 2007;40743-50.
In 2003, Neurontin sales were $2.7 Billion; 90% of prescriptions
were for off label use. NYT 5/30/03 p C1,2; NYT 5/14/04 C1.
Drug Samples Displace 1st Line Tx.
•
MDs giving samples:
– Much more likely to Rx second
choice drugs
– Believe second choice drugs are
most effective
•
JGIM 1999:125
– 2.5 x as likely to start uninsured
persons on brand names rather
than generics
• South Med J 9/2008.
• Am J Med 2005;118:881
•
Pre and post observation, 1
clinic before and after ending
drug samples. First line tx by
Joint National Committee on Tx
HBP.
– Fam Med 2002; 34:72931Replicated in Qual & Safety
Health Care 2007;16:266-70.
% 1st line Rx
70
60
50
40
30
20
10
0
Samples
Samples
Removed
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
Pharmacy Residents
• 89%: pharmaceutical company-sponsored
educational events enhance knowledge.
• 43%: information influences therapies.
• 26% trained in pharmacist-industry interactions
– Am J Health Sys Pharm 2007;64:1724-31. 496 pharmacy
residents
•
See Am J Pharm Ed 2007;71:Article 68 for a study of Pharmacy Deans views of
the potential influence of industry on Pharm D career choices or school policy.
Outline
• Industry Snapshot
• Political Power
• Sponsored Research
• Drug Detailing and Clinicians
• Drug Detailing and Medical Education
• Consumer Marketing
Drug Promotion $B
Consumer
Detailing
Med Jour
Samples
35
30
25
Note: Drug sample costs are retail!
20
15
10
5
0
1
2.8
4.2
1996
2000
2005
N Engl J Med 2007;357:673-81.
Adj to 2005 dollars
Drug Marketing Vs R & D %
DTC
Detailing
35
R&D
R&D
30
25
20
15
Detailing
10
5
DTC
0
DTC
Detailing
R&D
FDA and deceptive advertising.
•
•
•
Bush administration bars FDA
from telling a drug company to
stop running a deceptive ad
until it had run for 11 weeks
(earlier limit was 2 weeks).
Drug ad life is ~ 12 wks.
•US Congress
1/2004 (Waxman).
“Promotional spending is an effective
method of sharing information and
encouraging patients to talk to their
doctors.” --Glaxo spokesperson
160
140
120
100
80
60
40
20
0
1997
50% of public thinks
ads are approved by
FDA.
J Gen Med 1999;14 651-657.
2006
FDA Ad Violation Letters
N Engl J Med 2007;357:673-81.
Vioxx Advertising 2000
• Merck internal
Mill $
200
150
100
50
0
Merck Vioxx
Budweiser
Pepsi
documents
obtained at trial
show that it was
editing out data
on excess deaths
in 2001.
•
JAMA 2008;299:1813-17.
Meta-analysis: risk  x 2.38 heart attack, unstable angina, sudden
cardiac death, stroke, TIA with COX-2 inhibitors.
JAMA 2001;286:954-59.
September 30, 2004: Merck withdraws Vioxx because research confirms
that it  risk of heart attack and stroke.
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.
• (12) [7] % of patients request an advertised drug.
• Pts asking for advertised drug are (9) [17] times as likely
to get it.
• MDs are more ambivalent (40 vs 30%) [50 V 12%]
about value of a requested advertised drug.
•
(BMJ 2002; 324: 278-9.
500 visits, 78 MDs,
1431 patients.)
[CMAJ 2003;169: 40512 78 MDs, 1431
patients.]
See also: JAMA 2005;293):1995-02.
Pharmacists and Pediatric Off Label Prescriptions
•
•
70% familiar with off-label prescribing.
40% recalled dispensing pediatric off-label Rx in past month.
–
–
–
–
younger than recommended (85%, 297/351),
antihistamines, analgesics and beta(2)-agonists,
higher dose than recommended (74%, 229/310)
lower dose than recommended (41%, 103/258)
60% had been asked by public to sell OTCs (antihist, analges,
steroid preps) for off-label pediatric use.
• 78% believed they had a duty to inform prescriber
• 66% believed that they had a duty to inform parents.
•
• Brit J Clin Pharm 2007;64:90-5. 1500 randomly selected
community pharmacies 32.1% return.
Evening News and Prime Time Drug Ads
95%: Emotional appeals
82%: Made 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 an
aspect of life.
• 78%: Showed med use as
engendering social approval.
• 58%: Portrayed product as a
medical breakthrough.
•
•
•
•
– Ann Fam Med 2007;5:6-13.
Dr. Jarvik: The Rest of the Story
•
1976: received MD in from
University of Utah.
•
No internship or residency.
•
Never licensed to practice.
•
2006: Lipitor sales $13.6
Billion.
•
2010: Generic Atorvastatin
comes out, about 90%
cheaper.
– Pfizer lost battle to extend
patent; now fighting generic
manufacturer in court.
“I’m glad I take Lipitor, as a
doctor and as a dad.”
“For me, there is no substitute.”
Steven Miles, MD
[email protected]