Conflicts of interest: a case study in entanglement

1. Conflicts of interest: a case study in entanglement

2. How common are competing interests? • A quarter of US researchers have received pharmaceutical funding • Half have received “research related gifts” • An analysis of 789 articles from major medical journals found that a third of the lead authors had financial interests in their research—patents, shares, or payments for being on advisory boards or working as a director • Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research. A systematic review. JAMA 2003; 289: 454-65.

3. How common are competing interests? • 75 pieces giving views on calcium channel blockers • 89 authors • 69 (80%) responded • 45 (63%) had financial conflicts of interest • Only 2 of 70 articles disclosed the conflicts of interest • Stelfox HT, Chua G, O'Rourke K, Detsky AS. Conflict of interest in the debate over calcium channel antagonists. N Engl J Med 1998; 338: 101-105

4. Do authors declare conflicts of interest? • 3642 articles in the five leading general medical journals (Annals of Internal Medicine, BMJ, Lancet, JAMA, and the New England Journal of Medicine) • Only 52 (1.4%) declared authors' conflicts of interest • Hussain A, Smith R. Declaring financial competing interests: survey of five general medical journals. BMJ 2001;323:263-4.

5. Does conflict of interest matter? • Is there a relationship between whether authors are supportive of the use of calcium channel antagonists and whether they have a financial relationship with the manufacturers of the drugs? • Stelfox HT, Chua G, O'Rourke K, Detsky AS. Conflict of interest in the debate over calcium channel antagonists. N Engl J Med 1998; 338: 101-105

7. Sponsored research • A systematic review found 30 studies that compared research funded by drug companies research funded by other sources • Company sponsored research more likely to be published • Studies sponsored by pharmaceutical companies weremore likely to have outcomes favouring the sponsor than werestudies with other sponsors (odds ratio 4.05; 95% confidenceinterval 2.98 to 5.51; 18 comparisons) • None of the 13 studies that analysed methods reported that studies funded by industrywas of poorer quality

8. Does conflict of interest matter?: third generation contraceptive pills • At the end of 1998 three major studies without sponsoring from the industry found a higher risk of venous thrombosis for third generation contraceptives; three sponsored studies did not. • To date, of nine studies without sponsoring, one study found no difference and the other eight found relative risks from 1.5 to 4.0 (summary relative risk 2.4); four sponsored studies found relative risks between 0.8 and 1.5 (summary relative risk 1.1) • The sponsored study with a relative risk of 1.5 has been reanalysed several times, yielding lower relative risks; after this failed to convince, a new reanalysis was sponsored by another company. • One sponsored study finding an increased risk has not been published.

9. What proportion of trials in the five major general journals are funded by industry? • 75% in Annals of Internal Medicine, Lancet, JAMA, and NEJM • 30% in BMJ

10. In search of a better relationship between doctors and drug companies

11. Proposals for disentangling • Poll on bmj.com; 1479 responding • Would you like doctors to stop seeing drug company representatives, replacing them with more independent sources of health information? •  79% yes

12. Proposals for disentangling • Would you like doctors to stop receiving all forms of direct and indirect gifts from drug companies? •  Yes 84% • Would you like industry-funded education of doctors replaced by education funded by more independent sources? •  Yes 84%

13. Proposals for disentangling • Would you like doctors' professional associations and their peer-reviewed journals to reduce their reliance on industry funding to specified maximum levels? • Yes 85% • Would you like all financial relationships between doctors and drug companies conducted with transparent contracts that are disclosed to patients and the public? •  Yes 96%

14. Proposals for disentangling • Would you like mechanisms that genuinely create more distance and independence between doctor/researchers and their research sponsors? •  Yes 83% • Would you like government/public agency advisory panels, which are responsible for independent assessment of medical products or health policies, to reduce their reliance on doctors with financial ties to drug companies? •  Yes 87%

15. Proposals for disentangling • Would you like to see these sorts of changes become the basis of a charter for a new relationship between doctors and drug companies? • Yes 90%

16. Trouble 3—the sad story of HRT

17. The sad tale of HRT • Hormone replacement therapy for postmenopausal women was widely expected to reduce osteoporotic fractures, deaths from heart disease and stroke, and dementia • A great many observational studies supported these expectations

18. The sad tale of HRT • An early analysis in the BMJ in 1997 of data from trials suggested that far from from decreasing deaths from cardiovascular events HRT might increase them • Insults heaped on the authors and on the BMJ for publishing such “rubbish” • Many of these comments came from authors with undeclared competing interests • Elina Hemminki and Klim McPhersonImpact of postmenopausal hormone therapy on cardiovascular events and cancer: pooled data from clinical trialsBMJ, Jul 1997; 315: 149 - 153.

19. Results of Women’s Health Initiative • Began to be published in 2002 • Doubled deaths from breast cancer • No decrease (and possibly an increase) in deaths from heart disease • Increased thromboembolic disease and strokes • Increase in dementia • No improvement in quality of life

20. The sad tale of HRT • More than 100 million women worldwide have taken HRT • Professor Bruno Müller-Oerlinghausen, the head of the German Commission on Safety of Medicines,called HRT a "national and international tragedy." • Comparingit to thalidomide, he said that the "naiveand careless use of a medication that is perceived as naturaland optimal" had caused many unnecessary deaths among women.

21. The sad tale of HRT • In the 1960s American physicianRobert Wilson wrote the influential Forever Feminine, extollingthe virtues of HRT as a virtual fountain of youth for the "dulland unattractive" ageing woman • In 2002 it emerged that Wyeth paid Wilson for the book

22. The sad tale of HRT • In 2002 the New York based Society for Women's HealthResearch, whose "sole mission is to improve the health of womenthrough research," held a celebrity gala celebratingwomen's "coming of age" • The gala was entirely underwritten by Wyeth • A few dayslater Wyeth donated £250 000 to the society

23. The sad tale of HRT • Wyeth’s share price halved when the first results of the Women’s Health Initiative was published • Phyllis Greenberger, CEO of the Society of Women’s Health Research, andher staff went on national radio and television talk showsattacking the findings of the WHI study and its authors • "Insteadof taking the side of its constituents thesociety seemingly took the side of its donors—and of Wyethin particular."

24. The sad tale of HRT • Novo Nordisk hired German PR firm Haas & HealthPartner which sent doctors letters downplaying theWHI results • The letters emphasised that the "absolute riskfor women is quite minimal" and were signed by Dr Irene Haas(a historian, according to her company's website) • Doctors in Britain have been deluged with similar material

25. Conclusions • The drug industry does vital work • Doctors and drug companies have become too entangled • Some disentanglement would be good for everybody—patients, governments, doctors, and the industry