Is the relationship between the industry and prescribers (doctors) in trouble?

1. Is the relationship between the industry and prescribers (doctors) in trouble? Richard Smith Editor, BMJ www.bmj.com/talks

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

3. 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

4. A story of trouble I • AstraZeneca’s tactics in promoting rosuvastatin"raise disturbing questions about howdrugs enter clinical practice and what measures exist to protectpatients from inadequately investigated medicines" • The Galaxy series of clinical trials, which investigated theefficacy of rosuvastatin, included "weak data," "adventurousstatistics," and "marketing dressed up as research," • It has been an "unprincipled campaign" • Richard Horton, editor, Lancet • Lancet2003;362: 1341

5. 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

6. 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

7. 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

8. 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”

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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?

20. What are the current relationships between doctors and industry?

22. 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

23. 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.”)

24. 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

25. 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.”)

26. 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.”)

27. 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

28. 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

29. Conflicts of interest: a case study in entanglement

30. 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.

31. 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

32. 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.

33. 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

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

36. 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.

37. 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

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

39. 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

40. 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%

41. 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%

42. 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%

43. 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%

44. Trouble 3—the sad story of HRT

45. 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

46. 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.

47. 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

48. 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.

49. 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

50. 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