The pharmaceutical industry’s influence on medical publishing

1. The pharmaceutical industry’s influence on medical publishing Gavin Yamey MD Deputy editor, wjm (www.ewjm.com) Assistant editor, BMJ (bmj.com)

2. A question • You read a guideline by the AHA giving a “class I” recommendation for using tPA in acute stroke • You then find out that most authors had a financial relationship with Genentech, who make tPA • Now what do you do?

3. A question (2) • You read an extremely convincing RCT showing the huge benefit of flutamide in treating advanced pancreatic cancer • You then realize that the drug manufacturer did the randomization, gave statistical assistance, and did the data analysis • Now what do you do?

4. A question (3) • You’re having a busy day, but you agreed to see a drug rep who wants to persuade you to use Neurontin for conditions other than epilepsy • The rep offers you Neurontin pens, pads, and a clock. She then says she’ll pay for you to go to a symposium. • What do you do?

5. What I’d like to talk about • Industry influence over clinical trials (funding, design, analysis, publication) • Reviews • Guidelines • Ghostwriting • Dissemination/promotion to physicians • Some solutions

6. Industry influence: a summary •  Industry designs and funds studies likely to favor its products •  Companies analyze the data •  Ghostwriters are paid by industry to add favorable spin •  If the data are not favorable, industry suppresses or delays publication • $16 billion on drug promotion in 2000

7. Does this influence matter? • YES: Evidence shows that it affects the outcome of clinical trials, the conclusions of reviews, and the prescribing practices of physicians

8. Industry influence over clinical trials • Funding • Design • Data analysis • Publication

9. Industry funding of trials • Analysis of 107 controlled trials • Did authors favor new or old drug? • Did authors have industry support or not? • Trials funded by manufacturer of new drug were significantly more likely to favor new drug J Gen Intern Med 1986;1:155-8

10. Industry funding of trials (2) • Only 5% of industry-sponsored studies of cancer drugs reached unfavorable conclusions about the company's drugs; figure was 38% in studies with nonprofit funding JAMA 1999;282:1453-1457

11. Industry funding of trials (3) • Authors whose work supported the safety of calcium-channel blockers were more likely to be funded by the drugs' manufacturers than authors whose work did not support the safety of these medications N Engl J Med 1998;338:101-106

12. Industry funding of trials (4) • At the end of 1998, 3 major studies without industry support found a higher risk of venous thrombosis for 3rd generation contraceptives. • Three sponsored studies did not. BMJ 2000;320:381

13. Industry influence on trial design (1) • Testing drug in healthy population, rather than population that will receive it (drug appears to have fewer side effects) • Only 2.1% of subjects in trials of NSAIDs were 65yrs+, even though these drugs are more often used, and have a higher incidence of SEs, in the elderly CMAJ 1998;159:1373-1374

14. Industry influence over trial design (2) • Using surrogate end points, and only publishing favorable ones Int J Technol Assess Health Care 1996;12:209-237

15. Industry influence over trial design (3) • Testing new drug against insufficient dose of old drug (new drug appears more efficacious) • In one study, trials of NSAIDs always found the sponsor’s drug to be equal or better BUT in 48% of trials, the dose of the sponsor’s drug was higher Arch Intern Med 1994;154:157-163

16. Industry control over data analysis • Single author RCT of flutamide in advanced pancreatic cancer •  Unexpectedly favorable, dramatic result •  BUT: randomization, statistical assistance, and data analysis were all done by industry •  Study was heavily criticized BMJ 1998;316:1935-1938

17. Industry control over trial publication • 1987: Manufacturer of levothyroxine (Synthroid) contracted with UC researcher to compare it with existing thyroid preparations • 1990: No more effective • Sponsor refused to allow findings to be published JAMA 1997:277:1238-1243

18. Industry control over trial publication (2) • The Immune Response Corporation contracted with UCSF to perform an RCT of an immune modulator to treat AIDS • No effect • Company tried to suppress publication West J Med 2001;175:225-226

19. Industry control over trial publication (3) • 1996: Olivieri and colleagues found that deferiprone (used to treat thal major) could worsen hepatic fibrosis • Apotex (trial sponsor) threatened legal action if authors published the data CMAJ 1998;159:955-957

20. Industry influence over reviews • 106 reviews of passive smoking: does it cause harm? 63% concluded harmful, 37% harmless • Multiple regression analysis controlling for article quality, peer review status, article topic, yr of publication: the only factor associated with the conclusion was whether the author was affiliated to tobacco industry JAMA 1998;279:1566-70

21. Industry influence over guidelines • Survey of 192 authors of 44 clinical practice guidelines: 87% of authors had some form of interaction with the pharmaceutical industry • BUT in published versions of the guidelines, specific declarations about the personal financial interactions of authors with industry were made in only 2 cases JAMA 2002;287:612-7

22. Guidelines: a cautionary tale • The AHA rated the thrombolytic agent alteplase (tPA) as a class I (definitely recommended) intervention for stroke despite controversy about its safety and efficacy • Why did it make this recommendation?

23. Guidelines: a cautionary tale (2) • Most of the AHA's stroke experts had undisclosed ties to Genentech, the manufacturers of alteplase • Genentech contributed over $11m to the AHA in the decade before the AHA recommendation on alteplase

24. Guidelines: a cautionary tale (3) • Following public scrutiny, the AHA has been forced to withdraw statements that alteplase for stroke "saves lives" • Even a seemingly impartial non-profit organization that issues professional guidelines may have ties to the manufacturers of recommended interventions

25. Ghostwriting (the ghost-guest syndrome) •  A professional medical writer ("the ghost"): employed by industry, paid to write, not named as author [“the session musicians of the biomedical literature world”] • A prestigious author ("the guest"): does not analyze data, does not write the manuscript, may or may not review the manuscript

26. A rarity? • No •  In one study, 19% of original articles surveyed had named authors who would not meet ICMJE criteria for authorship (JAMA 1998;280:222-224) •  11% had ghostwriters, who were not named as authors •  Reviews, editorials, clinical guidelines: higher prevalence?

27. The harms of ghostwriting • Publishing articles that are over-zealous about a product could distort physician prescribing • Inaccurate or misleading information conveyed to physicians •  Ghostwriting distorts the scientific record

28. The Neurontin story (NY Times, 15 May 2002) • Neurontin: FDA-approved for a narrow use: seizure control in patients already on one drug • No good evidence for any other indication • Whistleblower case: Warner-Lambert hired 2 marketing firms to ghostwrite articles claiming the benefits of Neurontin for unapproved uses. • Company paid physicians $1000 to act as “guest” authors

29. Ghostwriters speak out • "I agreed to do two reviews for a supplement to appear under the names of respected ‘authors.’ I was given an outline, references, and a list of drug-company approved phrases. I was asked to sign an agreement stating that I would not disclose anything about the project. I was pressured to rework my drafts to position the product more favorably."

30. Ghostwriters speak out (2) • "I was told exactly what the drug company expected and given explicit instructions about what to play up and what to play down“

31. Drug reps, promotional materials, samples, gifts • Contrary to the beliefs of most heath care providers--samples, gifts, food, and discussions with drug reps exert significant influence on provider behavior • Promotional materials and presentations are often biased • www.nofreelunch.org

32. Drug samples • Industry gave out $7.2 billion worth of free samples in 2000 • Pharmaceutical companies' "generosity" to provide drug samples has a specific purpose: to change physician behavior to write more prescriptions for their particular drug.

33. Drug samples (2) • Physicians are more likely to prescribe a drug if a sample is available, even if they do not think the drug is the best one for the patient • What happens when the sample runs out? J Gen Int Med. 2000;15: 478-483.

34. Gifts: free trips to symposia • In one study in one hospital, accepting such a gift was associated with an increase in prescribing of 2 drugs manufactured by sponsor of symposium • Prescribing patterns were significantly different from national patterns Chest 1992 Jul;102(1):270-3

35. Contact with drug reps • Study of prescribing habits of 124 physicians after the introduction of temazepam • Contact with the drug rep regarding temazepam was the most consistent predictor of favorable reception. Soc Sci Med 1988;26(12):1183-9

36. Contact with drug reps (2) • Requests by physicians to add a new drug to the hospital formulary are strongly associated with physicians’ interactions with reps • JAMA 1994;272:355

37. Promotional material • Study of 106 statements made by drug reps during 13 presentations • 11% of statements were false, yet physicians rarely spotted them • JAMA 1995;273:1296-8

38. The Neurontin Story (2) NY Times, May 15 2002 • Whistleblower case: Physicians allowed pharmaceutical reps into their examining rooms to meet with patients, review medical charts, and recommend which medicines to prescribe • Called a “shadowing program” and it involved hundreds of patients

39. Are you “drug company dependent”? (CAGE) • Have you ever prescribed Celebrex? • Do you get Annoyed by people who complain about drug lunches and free gifts? • Is there a medication loGo on the pen you're using right now? • Do you drink your morning Eye-opener out of a Lipitor coffee mug? www.nofreelunch.org

40. The 4 steps to recovery • 1. We admit we are powerless over pharmaceutical paraphernalia-that our lives have become unmanageable. • 2. We make a searching and fearless moral inventory of ourselves and our desks. • 3. We are entirely ready to remove all these defects of character, as well as pens, penlights, and notepads. • 4. Having had a spiritual awakening as the result of these steps, we try to carry this message to others and to practice these principles in all our affairs.

41. Industry influence: some solutions • Contracts between industry and researchers allowing freedom to publish trials • Industry funds trials, but has no role at all in design, implementation, analysis, publication • Public funding of trials that matter • Reviews and guidelines: should they exclude sponsored authors or at least set a maximum level of industry support?

42. Disclosure, disclosure, disclosure • “Better to light a candle than to curse the darkness” • Yet competing interests (e.g. industry support) are still not being declared • Recent study of 89 authors (75 articles): 69 responded, 45 had financial conflicts of interest • But only 2 of the 70 articles had declarations N Engl J Med 1998;338:101-5

43. Industry influence: some solutions (2) • Codes of conduct on gifts/relationships to drug reps e.g. AMA Council on Ethical & Judicial Affairs: • “Any gifts accepted by physicians individually should primarily entail a benefit to patients and should not be of substantial value” • “Subsidies from industry should not be accepted directly or indirectly to pay for the costs of travel, lodging, or personal expenses of physicians who are attending conferences or meetings”

44. Conclusions • Industry influences medical publishing at all stages (funding, trial design, data analysis, publication, promotion of findings, ghostwriting) • Influence goes largely undisclosed • Industry influence arguably distorts the scientific record and distorts clinical medicine • Disclosure is a “partial panacea” (we have a better chance of deciding for ourselves)

45. A matter of life and death • "The integrity of a body of literature is itself our society's ultimate temporal forum for negotiating life and death, suffering and wellness.....the medical well-being of the society it serves is dependent on the question of who stands behind the word." (Mark Gruber, anthropologist)