Conflicts of interest: a case study in entanglement

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.

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

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.

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

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 were

more likely to have outcomes favouring the sponsor than were studies with other sponsors (odds ratio 4.05; 95% confidence interval 2.98 to 5.51; 18 comparisons)

• None of the 13 studies that analysed methods reported that studies funded by industry was of poorer quality

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.

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

In search of a better relationship between

doctors and drug companies

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

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%

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%

 

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%

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%

Trouble 3—the sad story of HRT

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

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.

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

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."

• Comparing it to thalidomide, he said that the "naive and careless use of a medication that is perceived as natural and optimal" had caused many unnecessary deaths among women.

The sad tale of HRT

• In the 1960s American physician

Robert Wilson wrote the influential Forever Feminine, extolling the virtues of HRT as a virtual fountain of youth for the "dull and unattractive" ageing woman

• In 2002 it emerged that Wyeth paid Wilson for the book

The sad tale of HRT• In 2002 the New York based Society for

Women's Health Research, whose "sole mission is to improve the health of women

through research," held a celebrity gala celebrating women's "coming of age"

• The gala was entirely underwritten by Wyeth

• A few days later Wyeth donated £250 000 to the society

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, and her staff went on national radio and television talk shows attacking the findings of the WHI study and its authors

• "Instead of taking the side of its constituents the

society seemingly took the side of its donors—and of Wyeth in particular."

The sad tale of HRT• Novo Nordisk hired German PR firm Haas

& Health Partner which sent doctors letters downplaying the WHI results

• The letters emphasised that the "absolute risk for 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

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