What drug has generated over $130 billion in sales? Lipitor

1. What drug has generated over $130 billion in sales? • Lipitor

2. Ethics and Professionalism:The Integrity of Medicine: Part IIMedical Industry and Medical Practice Richard L. Elliott, MD, PhD, FAPA Professor and Director, Medical Ethics Mercer University School of Medicine Adjunct Professor Mercer University School of Law

3. Follow-up to Research Ethics • Questions on cases/groups? • The integrity of medical research • Last hour – ethics and the protection of research subjects • Tuskegee, IRBs • Today – another threat to our integrity • Medicine and the medical industry • Tomorrow – threats to our integrity from within • Abuse of trainees • Impaired physicians

4. Relationships with the Pharmaceutical Industry • How good is the evidence in Evidence-Based Medicine? • Publication bias • Negative studies • Adequate review in industry funded journals • Duplicate publications • Ghost writing • What are we teaching? • Influence over content of medical education • CME talks, lunches • What are we prescribing? • Influence over prescribing practices • Free samples, gifts, DTC advertising

5. JAMA 2001;286(23):2947-55

6. Similar Effectiveness of Paroxetine, Fluoxetine, and Sertraline in Primary Care • K Kroenke et al. JAMA 2001;286:2947-2955 • ARTIST: A Randomized Trial Investigating SSRI Treatment • 573 depressed adult patients • 37 clinics • 1999 • Open label, randomized study • Sponsored by Eli Lilly

7. ARTIST - Comparative Outcomes per Eli Lilly • No statistically significant differences in clinical outcomes • No differences among anxious-depressed patients • No differences among older patients • No differences in patient satisfaction

9. Rankings of All Measures at 3 and 9 Months Paroxetine Fluoxetine Sertraline Best 7 15 58 Middle 27 39 14 Worst 39 19 1 p<10-21

10. ARTIST • Rare example of reporting a positive study as negative • What influence did Eli Lilly have on editorial decisions? • Choice of reviewers? • Referral to JAMA statistician? • Why did JAMA publish this?

11. (A Few) Big Pharma Scandals • Vioxx death data submitted to FDA concluded no significant risk • Intent-to-treat deaths in RCTs for Alzheimer’s • Subjects 34/1069 • Placebo 12/1078 • Hazard ratio 2.99 • Vagal nerve stimulation and editorials • Editor wrote favorable opinion piece, did nor disclose financial interests

12. Rosiglitazone (Avandia) • Peak sales $2.5 billion 2006 • 2007 meta-analysis of 42 triels • OR MI 1.43 (95% CI, 1.03 - 1.98; P = 0.03) • OR death from all CV causes 1.64 (95% CI, 0.98 to 2.74; P = 0.06) • Recent meta-analysis confirmed risk • Senate concluded GSK knew of risks, withheld data from FDA • FDA voted not to withdraw – one member of panel later found to have been paid by GSK • Meta-analysis (BMJ 2010) that commented on two meta-analyses found authors who had conflict more likely to give favorable opinion of risks (RR 3.5-6.5 depending on analysis)

13. Publication Bias • Perlis et al. Am J Psychiatry 2005;162:1957-60 • 162 randomized, double-blind, placebo-controlled clinical trials between 2001-2003 • AGP, AJP, J Clin Psych, J Clin Psychopharmacology • 60% received funding from industry • 47% authors reported potential conflict of interest • Those with potential conflict of interest were 4.9 times less likely to report negative results (6/75 vs. 26/87) • Comparable results in non-psychiatric literature

14. Effectiveness of Antidepressants • 74 FDA-registered trials of 12 antidepressants approved between 1987-2004 • 74 trials, 38 positive (statistically significant benefits for drug over placebo) • 37/38 published • Of 36 FDA-deemed negative trials: • 22 never published • 11 published in manner to appear positive • Only 3 negative trials published • Turner et al. NEJM 2008;358:252-60 • Thus, the published evidence for the efficacy of SSRIs is vastly different from the results of all trials: • 48/51 trials positive vs. 38/74

15. Efficacy of Cardiovascular Drugs • Results published in NEJM, JAMA, Lancet • 2000-2005 • If study funded by for-profit, 67.2 % favored newer treatment • If study funded by non-profit, 49% favored newer treatment • Ridker PM, Torres J:  JAMA 2006; 295. 2270-2274

16. JAMA. 2003;290:921-928 • 370 randomized drug trials from Cochrane data base • Experimental drug recommended as treatment of choice in 16% of trials funded by nonprofit organizations, 51% of trials funded by for-profit organizations (P.001; 2 test). • Adjusted analyses showed that trials funded by for-profit organizations were significantly more likely to recommend the experimental drug as treatment of choice (odds ratio, 5.3; 95% confidence interval, 2.0-14.4) compared with trials funded by nonprofit organizations. This association did not appear to reflect treatment effect or adverse events.

17. Publication of Clinical Trials • 451 study protocols submitted to one research committee • 375 publications resulted from 233 protocols (publication rate 52% - 233/451 protocols) • Odds ratios for publication: • Non-commercial funding 2.4 • Commercial funding 0.7 • Von Elm et al. Swiss Med Weekly

18. Reducing Publication Bias • Authors must have submitted trial to clinicaltrials.gov • Negative results available • Authors must report potential conflicts of interest • But funding sources can be buried in a long list of honoraria, speakers bureaus, research funding, … • Mandatory reporting of payments from medical industries

19. How effective are author disclosure policies? • JAMA. 2011 Mar 9;305(10):1008-17 • Reviewed 29 most recent meta-analyses in highestimpactmedical journals involving RCTs of pharmacological treatments. 2/29 MAs reported on potential conflicts among RCT authors. Conclusion: Journals might require CoI disclosure, but MAs relying on RCTs do not use this info • Otolaryngol Head Neck Surg 2009 Sep;141(3):311-5 • 25% of publications reviewed had disclosure discrepancies between disclosures at annual meeting presentation and subsequent publication • J Vasc Surg. 2011 Sep;54(3 Suppl):55S-8S • Inconsistent disclosures in 27% of disclosures

20. Peer Review • Peer review – supposed to ensure submission has scientific validity and ethical integrity • “Peer review” is a term used loosely by some. • The editor/symposium chair looked at it

21. Peer Review • One criterion for quality in a publication is peer review • Reviewers are selected randomly from a pool of pre-qualified experts having no conflicts of interest – avoids preselecting outcome of review • Some studies are so specialized that few experts exist and cannot be assigned randomly • Conflicts can be buried in a list of funding sources • Blinded review: Authors are removed from reviewers copies • Not hard to identify some authors based on references, previous work

22. Ghost Writing and Guest Authors • Ghost writer – person not identified who was involved in significant data or writing process • 11-13% of articles • Flanagan et al. JAMA 1998;280:222 • Ross JAMA 2008;299:1800 • “Hundreds of articles” The Observer Dec 7, 2003 • Guest author – inclusion of author who had minimal or no involvement in data or writing • Often honorarium • 16% research articles, 26% review articles, 21% editorials • ARTIST study? • Nemeroff, Text published by APA, written by drug company affiliate

23. Influence of Industry on Scientific Conclusions • Effects of passive smoking – harmful? • 106 reviews • 39/106 (37%) of reviews concluded no harm • 29/39 (74%) of these reviews had tobacco affiliations • 67/106 (63%) of reviews concluded passive smoke harmful • 2/67 (3%) had tobacco affiliations • Similar results in other biomedical research – affiliation with industry is best predictor of pro-industry finding (odds ratio 3.60) • Artist study? • Barnes et al. JAMA 1998;279:1556 • Bekelman et al. JAMA 2003;289:454

24. Evaluating bias in a publication or presentation • Lo JAMA 2013;310(10): 1019-1020 • Options for managing a condition, including generics and lifestyle changes; risks/benefits compared? • Limitations for studies of new drugs?

25. Accuracy of Advertising • 69 journal advertisements • 50.2% claims provided no source to support • When sources cited, 65% claims supported • Efficacy claims supported 53.2% • Can you believe claims in medical journal ads? • Flip a coin • Spielman et al. J NervMentDis 2008;196:267

26. Physicians and the Pharmaceutical Industry Relationship(s) often mutually beneficial Gifts Educational funding Research support Information Samples

27. Gifts from the Pharmaceutical Industry • Industry spends approximately $10,000/physician/year • 97% residents carry at least one item with industry logo • Six gifts/year • 14 meals/year • Much higher at MCCG • Wazana and PrimeauPsych Clin N Am 2002;25:647

28. Steinman et al. Am J Med 2001;110:551 MDs believed only 16% of other MDs unaffected by gifts, but 61% believed they were unaffected. Similarly, MDs believed 40% of there colleagues were at least moderately influenced by gifts, but very few believed they were similarly influenced.

29. Industry CME and Prescribing Patterns • $2.45 billion spent on continuing education for health professionals in 2006 • $1.4 billion paid for by industry (57%) • 2011 75% CME providers received commercial funding • After event, 4-5x greater prescribing of product

30. Formulary Requests • 40 physicians who requested a formulary addition from January 1989 through October 1990. Control physicians were 80 randomly selected physicians who had not made requests. • Physicians were more likely to have requested that drugs manufactured by specific companies be added to the formulary if they had met with pharmaceutical representatives from those companies (OR, 13.2; 95% CI, 4.8 to 36.3) or had accepted money from those companies (OR, 19.2; 95% CI, 2.3 to 156.9)

31. Pharmaceutical Research and Manufacturers of America (PhRMA) Guidelines • Pre-2002 • Golf, honoraria for attending presentations, trips, games • 2002 • Meals modest, without guests • Gifts of modest value (<$25-100) and primarily of benefit to patient care or practice • 2009 • No gifts (pens, notepads, stethoscopes, lights, etc.) which have value independent of patient education • May have office meals

32. AMA and the Pharmaceutical Industry • Gifts should primarily entail a benefit to patients and should not be of substantial value • Individual gifts of minimal value are acceptable if work-related • Some are calling for rejection of all gifts, meals, speaking honoraria, GME support • Supports National Clinical Trials Registry • Trials begun after 7/05 will be considered for publication only if publicly registered

33. Marcia Angell • “It would be naïve to conclude that bias is only a matter of a few isolated instances. It permeates the entire system.” • “Physicians can no longer rely on the medical literature for valid and reliable information.” • “Clinicians just do not know anymore how safe and effective prescription drugs really are, but the products are probably nowhere near as good as the published literature indicates.” • Angell M:    JAMA 300. 1069-1071.2008

34. AMSA Scorecard • Conflict of Interest Policies at Academic Medical Centers (http://amsascorecard.org/) • Gifts/Industry relationships • Gifts, consulting, speaking, disclosure • Samples, purchasing, access • Education • On/off campus, industry support, curriculum • MUSM Grade “C” • `Not widely disseminated to faculty/trainees

35. You can make a difference.