the drug industry and clinicians steven miles, md [email protected] slides available
TRANSCRIPT
Why is this ethics?
I will use regimens for the benefit of the ill in accordance with my ability and my judgment
I will teach them this skill and rules and lectures and all the rest of learning
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
Hippocrates 500 BCI do not believe that any clear knowledge of Nature can be obtained though any source other than a study of medicine and then only through a thorough mastery of this science. …Thus, if anyone were able to light upon the truth by experiment…he would always be able to make the best pronouncements of all.
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?
JAMA 2005;294:1333–42.
$95 Billion per year.
Drug Companies’ Profits(True/False: High drug barely cover R &D costs? FALSE)
Fortune Magazine
3rd rank
25 years of studies show corporate-sponsored research has more pro-corporate findings than
independent research.
Corporate trials 4 X aslikely to befavorable.
30 studies BMJ 2003;326:1167-71.
Corporate trials 1.8 X as likely to favor new med/ surg /dx method
Multivariate
158 drugs,87 surgical, 87 other tx.
CMAJ 2004; 170:477-80.
Corporate trials4.9 X as likely tofavor a psych med.
162 multivariate R-DB-PC Trials.
Am J Psych 2005; 1957-60.
Survival improved in 37% drug co trials, 17% non-company trials (p.<04)
134 oncology RCTs
Cancer 2009; 115:2783-01.
2003 200920052004 2006
See next slide.
Favorable Outcomes of Corporate Sponsored v Independent Research Published 2000-2005 in JAMA,
LANCET and NEJM
JAMA 2006;295:2270-74.
N=205, p.002
N=39, p.=07N=104, p.001
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.
• 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.
Internal Inconsistency: Sponsored studies ABSTRACTS are BETTER than the RESULTS/DATA.
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 cost-effectiveness of drug-eluting stents vs bare-metal stents.
P<.003
Delay Outcome Research and Results Publication:
Zetia and Vytorin
(Generic Simvastatin cost a third as much and was shown to decrease mortality.)
Results leak:No benefit,Possible Harm!
FDA approves with no mortality outcome data because it lowered cholesterol.
2002 2004 2006 2008
Makers beginoutcomes trial.
April: Trial Completed.
2005
Tx: 800,000 Americans/week
Earn $4 Billion/yr.
20% of US cholesterol drug market.
Ad budget $155 M Zetia & Vytorin
-Forbes
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.
• 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: 1647-56.
Number of studies
Favorable trials are published. Negative trials are not. Some companies present negative studies as
positive.
Avandia – 9/2010
Sales begin. Divided vote, poor data on risks. Minority report dissents.
WHO warns about heart effects.
GSK ordered to post unpub trials because of corporate suppression of data on antidepressant suicides.
GSK internal study (that ignores some MIs) finds 31% heart attack. P=NS. GSK conceals memo.
BMJ: Risks> benefits; withdraw it. UK: Ditto.
Europe stops sales.
FDA restricts sales; divided vote (Avandia speakers vote).
GSK to European Heart Journal: “Withdraw this editorial (critical of Avandia) and refrain from publishing it in any way.”
1999 201020052004 2007
Sales from $3B to $1B/Yr.
NEJM Meta-analysis shows 43% heart attack. Extra deaths~ 47,000. (A peer reviewer leaked review to Glaxo.)
FDA: Stronger label.
Sales:$500 M/Yr.
BMJ 2010:341:c4848.
2006
1 Million Rxs, 22%
Corporate-funded authors more likely to publish pro-corporate positions on risk
controversies.
Corporate sponsored researchers 2.6 X more likely to favor controversial Calcium channel blocker than those without funding. P.<.0001
NEJM 1998;338:101-6.
4 X more 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.
BMJ 2010; 340:c1344 doi:10.1136/bmj.c1344
1998 20102003
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.
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}
20052000 2002
BMJ 2002;325:249
Why is this ethics?
What is your duty to inform a patient who suffers a bad outcome possibly related to corrupted science?
I will use regimens for the benefit of the ill in accordance with my ability and my judgment
What is your duty with regard to reading corporate sponsored research?
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.– 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
Favorability toa branded statin
Grooming Residents for Detailing
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).• 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;196:267-73. 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
Invitation Course
Chest 1992;102:270-3. I use this old paper because it is the only such study.
Relative Sales
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 anti-convulsant 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
What is your duty to address the effects of sales representatives on clinicians and medical trainees?
I will teach them this skill and rules and lectures and all the rest of learning
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.
VioxxMerck 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
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.
12% price hike
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?
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
