The Drug Industry and Clinicians

1. The Drug Industry and Clinicians Steven Miles, MD miles001@umn.edu Slides available

2. Why did Drug Expenditures Increase from 1994-2005? # of Rx/ person from 7.9 to 12.4 Kaiser Family Foundation

3. Prescription Costs & Inflation  Declining inflation due to: -  Medicaid -  New drugs -  Generics. Rx in total US Health Costs $275 B US Dept of Labor

4. Drug Companies’ Profits (“Drug companies prices barely cover R &D costs and risks.”) 3rd rank Fortune Magazine

5. Drug Company Political Spending Federal Campaign Donations $ Millions Federal Lobbying $ Million 1100 Pharmaceutical lobbyists (100 Senators) (476 Congressmen) Center for Responsive Politics/ OpenSecrets.org Center for Public Integrity

6. 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

7. 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. Best Pharmaceuticals for Children Act 2002

8. 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. Medicare Prescription Drug and Modernization Act 2003 “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

9. FDA Drug Approvals New Drug Approval Times in Months http://www.fda.gov/cder/reports/reviewtimes/default.htm#FDA%20Review (newer data not available as of 11/2008)

10. 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

11. Who pays for drug research? 2005 $ Billion

12. Publication Bias in Sponsored Studies 4 X as likely to be favorable. 1.8 X as likely to favor new industry med/surg tx 4.9 x as likely to favor psych meds. Survival: Improved in 37% drug co trials, Improved in 17% non-co trials (p.<04) 2003 2004 2005 2009 30 studies BMJ 2003; 326:1167-71. (multivariate 158 drugs, 87 surgical, 87 other tx, 13 AIMs. CMAJ 2004; 170:477-80. Mulitvariate 162 R-DB-PC trials in Am J Psych 2005;1957-60. 134 oncol RCTs Cancer 2009; 115:2783-01.

13. Profit v not For Profit CV Research in JAMA, LANCET and NEJM 2000-2005 JAMA 2006;295:2270-74.

14. 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.

15. 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. P=.003 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.

16. 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)

17. 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)

18. Non-Dissemination-12 Antidepressants Number of 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. See also Psych Med 2006;36:1647-56.

19. 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 benefit Possible  Harm. Delay Outcome Research and Results Publication: Zetia and Vytorin 2008 2002 2004 2006 Makers begin events trial. FDA approval April: Trial Completed. • 2005:Ad budget $155 Million Zetia and Vytorin -Forbes

20. Public Relations • 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

21. 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.

22. 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.

23. 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

24. 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 Journals Strike Back: 9/2001

25. 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%.

26. 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.

27. 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. 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. .

28. 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

29. Comparing Physicians’ and Patients’ Attitudes Toward Drug Industry Gifts P<0.0001 for all 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

30. Positively Related Number of faculty Inversely Related Financial support from drug companies Clinical duties of residency director (less time for residents) Predictors of Internal Medicine Residency Board (ABIM) Program Pass Rates (3 year running average) Acad Med 2002;77:50

31. 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 Excludes: • Advertising, • Salaries of detailers, • Free samples, • Compensation for clinical trials, • Payments under $25, • Some educational scholarships • Unrestricted continuing med ed grants.

32. Drug Rep Course and Prescribing Invitation Course Months I have retained this old slide because it is the only such study. Chest 1992;102:270-73

33. Outline • Industry Snapshot • Political Power • Sponsored Research • Drug Detailing and Clinicians • Drug Detailing and Medical Education • Marketing • Professional • Direct to Consumer (DTC)

34. Drug Promotion $B Note: Drug sample costs are retail! N Engl J Med 2007;357:673-81. Adj to 2005 dollars

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

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

37. 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. Off-Label Marketing: Neurontin 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.

38. 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

39. 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.

40. 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

41. 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

42. 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.

43. 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 50% of public thinks ads are approved by FDA. J Gen Med 1999;14 651-657. N Engl J Med 2007;357:673-81.

44. Vioxx Advertising 2000 • Merck internal 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.

45. 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: 405-12 78 MDs, 1431 patients.] See also: JAMA 2005;293):1995-02.

46. 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.

47. Dr. Jarvik: The Rest of the Story “I’m glad I take Lipitor, as a doctor and as a dad.” • 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. “For me, there is no substitute.”

48. Steven Miles, MD Slides Available miles001@umn.edu