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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 Presentation

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Page 1: The Drug Industry and Clinicians

The Drug Industry and Clinicians

Steven Miles, [email protected] available

Page 2: The Drug Industry and Clinicians

Why did Drug Expenditures Increase from 1994-2005?

Kaiser Family Foundation

# of Rx/ person from 7.9 to 12.4

Page 3: The Drug Industry and Clinicians

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

Page 4: The Drug Industry and Clinicians

Drug Companies’ Profits(“Drug companies prices barely cover R &D costs and risks.”)

Fortune Magazine

3rd rank

Page 5: The Drug Industry and Clinicians

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)

Page 6: The Drug Industry and Clinicians

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

Page 7: The Drug Industry and Clinicians

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.

Page 8: The Drug Industry and Clinicians

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

Page 9: The Drug Industry and Clinicians

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

Page 10: The Drug Industry and Clinicians

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

Page 11: The Drug Industry and Clinicians

Who pays for drug research?

2005 $ Billion

Page 12: The Drug Industry and Clinicians

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

Page 13: The Drug Industry and Clinicians

Profit v not For Profit CV Research in JAMA, LANCET and NEJM 2000-2005

% of Studies Favoring Technology

0

20

40

60

80

100

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.

Page 14: The Drug Industry and Clinicians

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.

Page 15: The Drug Industry and Clinicians

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

0

5

10

15

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

Page 16: The Drug Industry and Clinicians

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)

Page 17: The Drug Industry and Clinicians

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)

Page 18: The Drug Industry and Clinicians

• 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.

0

10

20

30

40

PositiveStudies

NegativeStudies

Misleadingly Positive Publication

Not Published

Published

Number of studies

Non-Dissemination-12 Antidepressants

See also Psych Med 2006;36:1647-56.

Page 19: The Drug Industry and Clinicians

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

Page 20: The Drug Industry and Clinicians

• 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

Page 21: The Drug Industry and Clinicians

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.

Page 22: The Drug Industry and Clinicians

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.

Page 23: The Drug Industry and Clinicians

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

Page 24: The Drug Industry and Clinicians

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

Page 25: The Drug Industry and Clinicians

0%

20%

40%

60%

80%

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%.

Page 26: The Drug Industry and Clinicians

Grooming Residents for Detailing

1

2

3

4

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

Page 27: The Drug Industry and Clinicians

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.

Page 28: The Drug Industry and Clinicians

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

Page 29: The Drug Industry and Clinicians

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.

Page 30: The Drug Industry and Clinicians

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

Page 31: The Drug Industry and Clinicians

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.

Page 32: The Drug Industry and Clinicians

Drug Rep Course and Prescribing

0

1

2

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4

5

6

7

1 4 7 10 13 16 19 22 25 28 31

Rela

tive u

nit

s

Hosp ANation

Invitation

Course

Chest 1992;102:270-73

MonthsI have retained

this old slide because it is the only such study.

Page 33: The Drug Industry and Clinicians

Outline

• Industry Snapshot• Political Power• Sponsored Research • Drug Detailing and Clinicians• Drug Detailing and Medical Education• Marketing

– Professional– Direct to Consumer (DTC)

Page 34: The Drug Industry and Clinicians

Drug Promotion $B

1 2.8 4.20

5

10

15

20

25

30

35

1996 2000 2005

Consumer Detailing Med Jour Samples

N Engl J Med 2007;357:673-81.Adj to 2005 dollars

Note: Drug sample costs are retail!

Page 35: The Drug Industry and Clinicians

Drug Marketing Vs R & D %It is not true that drug companies spend more on ads

than R&D

Page 36: The Drug Industry and Clinicians

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.

0

10

20

30

40

50

60

70

Samples SamplesRemoved

% 1st line Rx

1 clinic pre and post ending samples. First line tx by Joint Nat Comm Tx HBP.

.

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.

Page 37: The Drug Industry and Clinicians

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.

Page 38: The Drug Industry and Clinicians

• 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

Page 39: The Drug Industry and Clinicians

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.

Page 40: The Drug Industry and Clinicians

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.

Page 41: The Drug Industry and Clinicians

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.

Page 42: The Drug Industry and Clinicians

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.

Page 43: The Drug Industry and Clinicians

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.

Page 44: The Drug Industry and Clinicians

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.

0

5 0

1 0 0

1 5 0

2 0 0

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.

Page 45: The Drug Industry and Clinicians

(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.

Page 46: The Drug Industry and Clinicians

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.

Page 47: The Drug Industry and Clinicians

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.”

Page 48: The Drug Industry and Clinicians

Steven Miles, MD

Slides [email protected]