Is the relationship between the industry

and prescribers (doctors) in trouble?

Richard SmithEditor, BMJ

www.bmj.com/talks

Answer

•It could certainly be improved--made more “professional”

What I want to talk about

• A story of trouble• The context of the relationship• How is the world changing?• Another story of trouble• What are the current relationships between doctors and

industry?• Conflicts of interest: a case study of entanglement• How might the relationships between doctors and

industry be improved?• Another story of trouble• Conclusions

A story of trouble I

• AstraZeneca’s tactics in promoting rosuvastatin

"raise disturbing questions about how drugs enter clinical practice and what measures exist to protect

patients from inadequately investigated medicines"

• The Galaxy series of clinical trials, which investigated the efficacy of rosuvastatin, included "weak data," "adventurous statistics," and "marketing dressed up as research,"

• It has been an "unprincipled campaign" • Richard Horton, editor, Lancet

• Lancet 2003;362: 1341

A story of trouble I

• Regulators, doctors, and patients as well as AstraZeneca have been poorly served by your flawed and incorrect editorial. I deplore the fact that a respected scientific journal such as The Lancet should make such an outrageous critique of a serious, well studied, and important medicine

• Tom McKillop, CEO, AstraZeneca

The context

• Virtually all new drugs in the past 50 years have been discovered or manufactured by the drug industry

• The industry has consistently been one of the most profitable industries and is truly global

• It has great political power, particularly in the United States

The context

• Medicine is also global, but there is no international “health organisation” (WHO, WMA) that has the resources and power of the industry

• Research-based companies are merging--driven in large part by the costs of discovering new drugs and bringing the to market

The context

• The power of generic companies (many in India and Brazil) is rising

• The cost of bringing a drug to market is huge and rising--which may be no bad thing for large companies as it raises “the barrier to entry”

The context

• The industry has been largely cut off from the people who take their products

• The industry has concentrated its enormous marketing resources on doctors--because they have written the prescriptions

• The “spend” per doctor is enormous• Doctors have become addicted to the largesse

The context

• Companies must produce a good return on investment for shareholders

• They ideally do this through producing much needed new drugs--from which everybody benefits

• But their legitimate commercial values sometimes (even often) conflict with the values of health care workers and systems

The context: examples of value clashes

• It cannot make commercial sense to produce new drugs for very rare conditions or conditions affecting those who have no money to pay

• It does make sense to produce a “me too” drug for a profitable market and market it as hard as possible

• Restrictions on marketing efforts are legitimately strained against

The context: examples of value clashes

• Drug treatments are favoured over non-drug treatments

• Companies are understandably reluctant to fund large head to head trials

• Companies are clever enough to “honestly” get the results from trials they fund

• Companies favour secrecy for commercial reasons; doctors and patients want transparency

The world is changing

• Drug companies have a productivity crisis--companies were producing 3 new chemical entities each year on average; now it’s 0.3 (Dresdner Kleinwort Wasserstein)

• In these circumstances companies may need to market still harder the products they have and “invent” new diseases

The world is changing

• The current business model of research-based companies is unsustainable--Dresdner Kleinwort Wasserstein– New discoveries are down– 12-15% increase in sales (half of it coming from price

increases) is becoming impossible to sustain because of political pressure (4th hurdles, NICE, etc)

• Answer: more mergers, creating “monopolies” in particular therapeutic areas

The world is changing

• Direct to consumer advertising has arrived in the US and New Zealand and will probably be unstoppable across the world

• Companies have to increase their marketing spend dramatically

• New “relationships” are created with consumers

• Doctors generally resent companies “going over their heads” and creating expectations that doctors must meet

The world is changing

• Increasing numbers of bodies—for example, NICE and HMOs—are interested in controlling prescribing

• A WHO report praises NICE but criticises it for being too close to industry

• Other prescribers are appearing• Doctors may not be the target they

once were

The world is changing

• There is growing understanding of how the industry can get the results it wants—three papers for the Christmas BMJ

• Governments are increasingly interested in public funding of trials

• ALLHAT and the Women’s Health Initiative have given that interest a boost

Trouble 2

• A journal publishes a paper that combines two trials A and B that show that a drug manufactured by Y, the sponsors of the studies, is better than a drug manufactured by Z

• A correspondent points out that trial A has already been published—a case of duplicate publication?

• Trial A and the paper (A and B) had only one common author—an employee of Y

Trouble 2

• It also emerges that trial B did not find that Y had better outcomes than Z

• Then it emerges that on the FDA website the trials A and B both included other outcome measures—possibly ones that matter more to patients—where Z had better outcomes than Y

• How should the editors/publishers respond?

What are the current

relationships between doctors

and industry?

16 forms of entanglement between doctors and drug companies

• Face to face visits from drug company representatives

• Acceptance of direct gifts of equipment, travel, or accommodation (“Will you advertise my drug on your person for a year if I pay you 20p?”)

• Acceptance of indirect gifts, through sponsorship of software or travel

16 forms of entanglement between doctors and drug companies

• Attendance at sponsored dinners and social or recreational events (“If they have to pay the full whack they won’t come?”)

• Attendance at sponsored educational events, continuing medical education, workshops, or seminars (“Could you hurry up so we can get to the vol au vents?”)

• Attendance at sponsored scientific conferences (“Bugger Bognor, but the Gritti Palace in Venice sounds good.”)

16 forms of entanglement between doctors and drug companies

• Ownership of stock or equity holdings• Conducting sponsored research (“It’s so hard

to get money from the MRC and £800 for registering a patient is not bad.”)

• Company funding for medical schools, academic chairs, or lecture halls

• Membership of sponsored professional societies and associations

• Advising a sponsored disease foundation or patients' group

16 forms of entanglement between doctors and drug companies

• Involvement with or use of sponsored clinical guidelines

• Undertaking paid consultancy work for companies (“A return flight on Concorde, five nights at the Ritz Carlton, and 20 grand is not bad for two hours of blah.”)

• Membership of company advisory boards of "thought leaders" or "speakers' bureaux” (“Flattery and money: I can resist everything except temptation.”)

16 forms of entanglement between doctors and drug companies

• Authoring "ghostwritten" scientific articles (A critic on Naomi Campbell’s autobiography: “If she can’t be bothered to write it I can’t be bothered to read it.”)

• Medical journals' reliance on drug company advertising, company purchased reprints, and sponsored supplements (“It’s a million quid and £800 000 profit for reprints of a major trial. Without it I might have to lay off staff. But we’re not influenced in our decision making.”)

Does all this matter?

• Virtually all new drugs, which have been so important for medicine, have come from drug companies

• Drug companies must have the right to market their products

• Prescribing is influenced--often to be unnecessarily expensive

Does all this matter?

• Information is biased• Doctors are too dependent on drug

companies for both education and information

• Companies spend more on marketing than on research

• Costs are inflated

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

• Joel Lexchin, Lisa A Bero, Benjamin Djulbegovic, and Otavio ClarkPharmaceutical industry sponsorship and research outcome and quality: systematic reviewBMJ, May 2003; 326: 1167 - 1170.

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.• Vandenbroucke JP, Helmerhorst FM, Frits R Rosendaal FR. Competing interests

and controversy about third generation oral contraceptives. BMJ 2000; 320: 381.

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