the drug industry and clinicians
DESCRIPTION
The Drug Industry and Clinicians. Steven Miles, MD [email protected] Slides available. Why did Drug Expenditures Increase from 1994-2005?. # of Rx/ person from 7.9 to 12.4. Kaiser Family Foundation. Prescription Costs & Inflation. Declining inflation due to: - Medicaid - PowerPoint PPT PresentationTRANSCRIPT
The Drug Industry and Clinicians
Steven Miles, [email protected] available
Why did Drug Expenditures Increase from 1994-2005?
Kaiser Family Foundation
# of Rx/ person from 7.9 to 12.4
Prescription Costs & Inflation
Declining inflation due to: - Medicaid - New drugs - Generics.
$275 B
US Dept of Labor
Rx in total US Health Costs
Drug inflation compared to CPI
0
5
10
15
1985 1990 1995 2000 2005 2007
Drug inflation % > CPI
Drug Companies’ Profits(“Drug companies prices barely cover R &D costs and risks.”)
Fortune Magazine
3rd rank
Drug Company Political Spending
$0
$40
$80
$120
$160
2003-4 2005-6
Center for Responsive Politics/ OpenSecrets.org
$0
$10
$20
$30
1994 1998 2002 2006
From Indiv From PACs Soft $
NA
Federal Lobbying$ Million
Federal Campaign Donations$ Millions
Center for Public Integrity
1100 Pharmaceutical lobbyists(100 Senators)
(476 Congressmen)
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: $3.2 M /drug.• Net economic return to cost: $17 to $1 (range 4-65).
– Amer Ht J 2008;156:682-8. 9 po antihbp drugs under the Pediatric Exclusivity Provision from 1997 to 2004.
• Coalition for Children’s Health, "leading coalition in Washington on children’s health policy," funded by drug industry, chaired by ex drug lobbyist. Closed after law passed.
• 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 cost-effectiveness 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
120
237
3733
New Drug ModifiedNew Combo Nothing new
05
101520253035
1986 1990 1994 1998 2000
Months to approval
http://www.fda.gov/cder/reports/reviewtimes/default.htm#FDA%20Review (newer data not available as of 11/2008)
New Drug Approval Times in Months
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?
2005 $ Billion
Publication Bias in Sponsored Studies
4 X as likelyto befavorable.
30 studies BMJ 2003;326:1167-
71.
1.8 X as likely to favor new industrymed/surg tx
(multivariate158 drugs,87 surgical, 87 other tx, 13 AIMs. CMAJ 2004;170:477-80.
4.9 x as likelyto favorpsych meds.
Mulitvariate162 R-DB-PCtrials in Am JPsych2005;1957-60.
Survival: Improved in 37% drug co trials, Improved in 17% non-co trials (p.<04)
134 oncol RCTs Cancer 2009;115:2783-01.
2003 200920052004
Profit v not For Profit CV Research in JAMA, LANCET and NEJM 2000-2005
% of Studies Favoring Technology
0
20
40
60
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Drugs Devices Other: eg. Lab tests
Not for Profit Corporate
N= 205, P=.002.
N= 39, P= .07
N = 104, P =.001
JAMA 2006;295:2270-74.
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 7.1-168], 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; Pharmaco- economics 1997;11:289-91.
Cor Stent Cost Benefit Studies
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Corp Spon Non CorpSpon
Favor wide use Do not favor
CMAJ 2007;176:199-205. 19 studies 1/1/20-7/1/06 about insurance cost-effectiveness of drug-eluting stents vs bare-metal stents.
P=.003
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)
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)
• Publication record:– 94% of trials were positive
• Truth: – 51% of trials were positive.
• 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.
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PositiveStudies
NegativeStudies
Misleadingly Positive Publication
Not Published
Published
Number of studies
Non-Dissemination-12 Antidepressants
See also Psych Med 2006;36:1647-56.
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.
Results leak:No benefitPossible Harm.
FDA approval
2002 2004 2006 2008
Makers beginevents trial.
April: Trial Completed.
• 2005:Ad budget $155 Million Zetia and Vytorin -Forbes
• Omnicom, Interpublic, and WPP (Madison Avenue’s 3 largest PR firms) have spent $10s of millions buying companies to perform drug clinical trials.
• The PR companies– Write clinical papers– Offer CME– Recruit peer MDs to promote drugs.
• 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.
“We provide services that go from the beginning of drug development all the way to the launch of your product.” CEO
Public Relations
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.
Relationships between Authors of Clinical Practice Guidelines and Pharmaceutical
Industry• 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}
• 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
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
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20%
40%
60%
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100%
Most drug co' GrandRounds are helpful
& educational.
OK to acceptgifts/lunches
because they havelittle influence.
Co' materialeducational.
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 med schools. Response rate 72.3%.
Grooming Residents for Detailing
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PG1 PG2 PG3
Lunch Talk @ Noon
Very inappropriate
Very appropriate
Acad Med 2006;81;595-602. 118 IM resSee also Acad Med 2007;82(10):S1-3; 2007;82:94-9.
.006
.004
Housestaff views of their own virtues compared to their peers
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. .
• 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.
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
Comparing Physicians’ and Patients’ Attitudes Toward Drug Industry Gifts
J Gen Int Med 1998;13:151
P<0.0001 for all
Half of pts knew of such gifts. Of those unaware, 24% said this diminished their perception of MDs.
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
Drug Detailing, Vermont 2006
• 81 drug makers• Spent $2.47 M on
honoraria, consulting fees, travel expenses, etc on physicians, hospitals, universities etc.
• 90% to prescribers• Attorney General
Vermont 2007
Cash Food Other
Excludes:•Advertising, •Salaries of detailers, •Free samples, •Compensation for clinical trials, •Payments under $25, •Some educational scholarships •Unrestricted continuing med ed grants.
Drug Rep Course and Prescribing
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Invitation
Course
Chest 1992;102:270-73
MonthsI have retained
this old slide because it is the only such study.
Outline
• Industry Snapshot• Political Power• Sponsored Research • Drug Detailing and Clinicians• Drug Detailing and Medical Education• Marketing
– Professional– Direct to Consumer (DTC)
Drug Promotion $B
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Consumer Detailing Med Jour Samples
N Engl J Med 2007;357:673-81.Adj to 2005 dollars
Note: Drug sample costs are retail!
Drug Marketing Vs R & D %It is not true that drug companies spend more on ads
than R&D
Drug SamplesMDs 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– Southern Med J 9/2008.– Am J Med 2005;118:881
• Much more willing to say drug reps are valuable in teaching MDs about new drugs.
– Acad Med 2009;994-1002.
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Samples SamplesRemoved
% 1st line Rx
1 clinic pre and post ending samples. First line tx by Joint Nat Comm Tx HBP.
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Removing Samples• Shifts prescribing in direction of
rational national guidelines. – Fam Med 2002; 34:729-31. Replicated in
Qual & Safety Health Care 2007;16:266-70
• Results 1 to 15% in prescribing of generics, p>.001.
– Arch Intern Med. 2009;169(13):1241-1242.
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.
• PLoS 2007;40743-50.
• ‘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.
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.
• WASHINGTON (Dow Jones)--The Department of Justice said Pfizer promoted Bextra for several uses and dosages that the FDA specifically declined to approve because of safety concerns.
• Pfizer also improperly promoted the anti-psychotic drug Geodon, the antibiotic drug Zyvox and the anti-epileptic drug Lyrica, the department said.
• The department said Pfizer will pay $1.3 billion in criminal fines and another $1 billion in civil fines.
• Pfizer pulled Bextra from the market in 2005 because the FDA concluded its risks, including a rare but serious skin reaction, outweighed its benefit.
September 2, 2009
Psychiatric Drug Ads in Medical Journals
• Support of Claims with Cited Sources– 94 efficacy claims—53% supported by cite.– 38 safety claims—84% supported by cite.– Authors asked companies for supporting
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” • 69 unique ads in Arch Gen Psych, Am J Psych, NEJM, JAMA, 2006. J Nerv
Ment Dis 2008;196:267-273.
American Psychiatric Assn
• Pharmaceutical Revenue – 28% ($14 M) of
38,000 member org budget.
• Amednews.com 2008 Aug 18.
• 2002 Convention– 268 booths, – 8 companies– 16 violations of
APA rules– 4 violations of FDA
rule on promoting off label activetiy.
– J Pub Health Pol 2005;26:400-3.
American Psychiatric Assn
• Pharmaceutical Revenue – 28% ($14 M) of
38,000 member org budget.
• Amednews.com 2008 Aug 18.
• 2002 Convention– 268 booths, – 8 companies– 16 violations of
APA rules– 4 violations of FDA
rule on promoting off label activetiy.
– J Pub Health Pol 2005;26:400-3.
Psychiatric Drug Ads in Medical Journals
• Support of Claims with Cited Sources– 94 efficacy claims—53% supported by cite.– 38 safety claims—84% supported by cite.– Authors asked companies for supporting
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” • 69 unique ads in Arch Gen Psych, Am J Psych, NEJM, JAMA, 2006. J Nerv Ment Dis
2008;196:267-273.
020406080
100120140160
1997 2006
FDA Ad Violation Letters
N Engl J Med 2007;357:673-81.
FDA and deceptive advertising.
• “Promotional spending is an effective method of sharing information and encouraging patients to talk to their doctors.” --Glaxo spokesperson
• 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).
50% of public thinks ads are approved by FDA.
J Gen Med 1999;14 651-657.
Vioxx Advertising 2000
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.
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M erck V ioxx B u d w eiser P ep si
M ill $• Merck internal
documents obtained at trial show that it was editing out data on excess deaths in 2001. • JAMA 2008;299:1813-17.
(BMJ 2002; 324: 278-9. 500 visits, 78 MDs, 1431 patients.)
[CMAJ 2003;169: 405-12 78 MDs, 1431 patients.]
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.
See also: JAMA 2005;293):1995-02.
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
Slides [email protected]