The%20pharmaceutical%20industry

1
The pharmaceutical industrys influence on
medical publishing

• Gavin Yamey MD
• Deputy editor, wjm (www.ewjm.com)
• Assistant editor, BMJ (bmj.com)

2
A question

• You read a guideline by the AHA giving a class
  I recommendation for using tPA in acute stroke
• You then find out that most authors had a
  financial relationship with Genentech, who make
  tPA
• Now what do you do?

3
A question (2)

• You read an extremely convincing RCT showing the
  huge benefit of flutamide in treating advanced
  pancreatic cancer
• You then realize that the drug manufacturer did
  the randomization, gave statistical assistance,
  and did the data analysis
• Now what do you do?

4
A question (3)

• Youre having a busy day, but you agreed to see a
  drug rep who wants to persuade you to use
  Neurontin for conditions other than epilepsy
• The rep offers you Neurontin pens, pads, and a
  clock. She then says shell pay for you to go to
  a symposium.
• What do you do?

5
What Id like to talk about

• Industry influence over clinical trials (funding,
  design, analysis, publication)
• Reviews
• Guidelines
• Ghostwriting
• Dissemination/promotion to physicians
• Some solutions

6
Industry influence a summary

•  Industry designs and funds studies likely to
  favor its products
•  Companies analyze the data
•  Ghostwriters are paid by industry to add
  favorable spin
•  If the data are not favorable, industry
  suppresses or delays publication
• 16 billion on drug promotion in 2000

7
Does this influence matter?

• YES Evidence shows that it affects the outcome
  of clinical trials, the conclusions of reviews,
  and the prescribing practices of physicians

8
Industry influence over clinical trials

• Funding
• Design
• Data analysis
• Publication

9
Industry funding of trials

• Analysis of 107 controlled trials
• Did authors favor new or old drug?
• Did authors have industry support or not?
• Trials funded by manufacturer of new drug were
  significantly more likely to favor new drug
• J Gen Intern Med 19861155-8

10
Industry funding of trials (2)

• Only 5 of industry-sponsored studies of cancer
  drugs reached unfavorable conclusions about the
  company's drugs figure was 38 in studies with
  nonprofit funding
• JAMA 19992821453-1457

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Industry funding of trials (3)

• Authors whose work supported the safety of
  calcium-channel blockers were more likely to be
  funded by the drugs' manufacturers than authors
  whose work did not support the safety of these
  medications
• N Engl J Med 1998338101-106

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Industry funding of trials (4)

• At the end of 1998, 3 major studies without
  industry support found a higher risk of venous
  thrombosis for 3rd generation contraceptives.
• Three sponsored studies did not.
• BMJ 2000320381

13
Industry influence on trial design (1)

• Testing drug in healthy population, rather than
  population that will receive it (drug appears to
  have fewer side effects)
• Only 2.1 of subjects in trials of NSAIDs were
  65yrs, even though these drugs are more often
  used, and have a higher incidence of SEs, in the
  elderly
• CMAJ 19981591373-1374

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Industry influence over trial design (2)

• Using surrogate end points, and only publishing
  favorable ones
• Int J Technol Assess Health Care 199612209-237

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Industry influence over trial design (3)

• Testing new drug against insufficient dose of old
  drug (new drug appears more efficacious)
• In one study, trials of NSAIDs always found the
  sponsors drug to be equal or better BUT in 48
  of trials, the dose of the sponsors drug was
  higher
• Arch Intern Med 1994154157-163

16
Industry control over data analysis

•  Single author RCT of flutamide in advanced
  pancreatic cancer
•  Unexpectedly favorable, dramatic result
•  BUT randomization, statistical assistance, and
  data analysis were all done by industry
•  Study was heavily criticized
• BMJ 19983161935-1938

17
Industry control over trial publication

• 1987 Manufacturer of levothyroxine (Synthroid)
  contracted with UC researcher to compare it with
  existing thyroid preparations
• 1990 No more effective
• Sponsor refused to allow findings to be published
• JAMA 19972771238-1243

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Industry control over trial publication (2)

• The Immune Response Corporation contracted with
  UCSF to perform an RCT of an immune modulator to
  treat AIDS
• No effect
• Company tried to suppress publication
• West J Med 2001175225-226

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Industry control over trial publication (3)

• 1996 Olivieri and colleagues found that
  deferiprone (used to treat thal major) could
  worsen hepatic fibrosis
• Apotex (trial sponsor) threatened legal action if
  authors published the data
• CMAJ 1998159955-957

20
Industry influence over reviews

• 106 reviews of passive smoking does it cause
  harm? 63 concluded harmful, 37 harmless
• Multiple regression analysis controlling for
  article quality, peer review status, article
  topic, yr of publication the only factor
  associated with the conclusion was whether the
  author was affiliated to tobacco industry
• JAMA 19982791566-70

21
Industry influence over guidelines

• Survey of 192 authors of 44 clinical practice
  guidelines 87 of authors had some form of
  interaction with the pharmaceutical industry
• BUT in published versions of the guidelines,
  specific declarations about the personal
  financial interactions of authors with industry
  were made in only 2 cases
• JAMA 2002287612-7

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Guidelines a cautionary tale

• The AHA rated the thrombolytic agent alteplase
  (tPA) as a class I (definitely recommended)
  intervention for stroke despite controversy about
  its safety and efficacy
• Why did it make this recommendation?

23
Guidelines a cautionary tale (2)

• Most of the AHA's stroke experts had undisclosed
  ties to Genentech, the manufacturers of alteplase
  
• Genentech contributed over 11m to the AHA in the
  decade before the AHA recommendation on alteplase

24
Guidelines a cautionary tale (3)

• Following public scrutiny, the AHA has been
  forced to withdraw statements that alteplase for
  stroke "saves lives"
• Even a seemingly impartial non-profit
  organization that issues professional guidelines
  may have ties to the manufacturers of recommended
  interventions

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Ghostwriting (the ghost-guest syndrome)

•  A professional medical writer ("the ghost")
  employed by industry, paid to write, not named as
  author the session musicians of the biomedical
  literature world
• A prestigious author ("the guest") does not
  analyze data, does not write the manuscript, may
  or may not review the manuscript

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A rarity?

• No
•  In one study, 19 of original articles surveyed
  had named authors who would not meet ICMJE
  criteria for authorship (JAMA 1998280222-224)
•  11 had ghostwriters, who were not named as
  authors
•  Reviews, editorials, clinical guidelines higher
  prevalence?

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The harms of ghostwriting

•  Publishing articles that are over-zealous about
  a product could distort physician prescribing
• Inaccurate or misleading information conveyed to
  physicians
•  Ghostwriting distorts the scientific record

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The Neurontin story (NY Times, 15 May 2002)

• Neurontin FDA-approved for a narrow use seizure
  control in patients already on one drug
• No good evidence for any other indication
• Whistleblower case Warner-Lambert hired 2
  marketing firms to ghostwrite articles claiming
  the benefits of Neurontin for unapproved uses.
• Company paid physicians 1000 to act as guest
  authors

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Ghostwriters speak out

• "I agreed to do two reviews for a supplement to
  appear under the names of respected authors. I
  was given an outline, references, and a list of
  drug-company approved phrases. I was asked to
  sign an agreement stating that I would not
  disclose anything about the project. I was
  pressured to rework my drafts to position the
  product more favorably."

30
Ghostwriters speak out (2)

• "I was told exactly what the drug company
  expected and given explicit instructions about
  what to play up and what to play down

31
Drug reps, promotional materials, samples,
gifts

• Contrary to the beliefs of most heath care
  providers--samples, gifts, food, and discussions
  with drug reps exert significant influence on
  provider behavior
• Promotional materials and presentations are often
  biased
• www.nofreelunch.org

32
Drug samples

• Industry gave out 7.2 billion worth of free
  samples in 2000
• Pharmaceutical companies' "generosity" to provide
  drug samples has a specific purpose to change
  physician behavior to write more prescriptions
  for their particular drug.

33
Drug samples (2)

• Physicians are more likely to prescribe a drug if
  a sample is available, even if they do not think
  the drug is the best one for the patient
• What happens when the sample runs out?
• J Gen Int Med. 200015 478-483.

34
Gifts free trips to symposia

• In one study in one hospital, accepting such a
  gift was associated with an increase in
  prescribing of 2 drugs manufactured by sponsor of
  symposium
• Prescribing patterns were significantly different
  from national patterns
  Chest 1992 Jul102(1)270-3

35
Contact with drug reps

• Study of prescribing habits of 124 physicians
  after the introduction of temazepam
• Contact with the drug rep regarding temazepam was
  the most consistent predictor of favorable
  reception.
• Soc Sci Med 198826(12)1183-9

36
Contact with drug reps (2)

• Requests by physicians to add a new drug to the
  hospital formulary are strongly associated with
  physicians interactions with reps
• JAMA 1994272355

37
Promotional material

• Study of 106 statements made by drug reps during
  13 presentations
• 11 of statements were false, yet physicians
  rarely spotted them
• JAMA 19952731296-8

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The Neurontin Story (2) NY Times, May 15 2002

• Whistleblower case Physicians allowed
  pharmaceutical reps into their examining rooms to
  meet with patients, review medical charts, and
  recommend which medicines to prescribe
• Called a shadowing program and it involved
  hundreds of patients

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Are you drug company dependent? (CAGE)

• Have you ever prescribed Celebrex?
• Do you get Annoyed by people who complain about
  drug lunches and free gifts?
• Is there a medication loGo on the pen you're
  using right now?
• Do you drink your morning Eye-opener out of a
  Lipitor coffee mug?
• www.nofreelunch.org

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The 4 steps to recovery

• 1. We admit we are powerless over pharmaceutical
  paraphernalia-that our lives have become
  unmanageable.
• 2. We make a searching and fearless moral
  inventory of ourselves and our desks.
• 3. We are entirely ready to remove all these
  defects of character, as well as pens, penlights,
  and notepads.
• 4. Having had a spiritual awakening as the result
  of these steps, we try to carry this message to
  others and to practice these principles in all
  our affairs.

41
Industry influence
some solutions

• Contracts between industry and researchers
  allowing freedom to publish trials
• Industry funds trials, but has no role at all in
  design, implementation, analysis, publication
• Public funding of trials that matter
• Reviews and guidelines should they exclude
  sponsored authors or at least set a maximum level
  of industry support?

42
Disclosure, disclosure, disclosure

• Better to light a candle than to curse the
  darkness
• Yet competing interests (e.g. industry support)
  are still not being declared
• Recent study of 89 authors (75 articles)
  69 responded, 45 had financial conflicts
  of interest
• But only 2 of the 70 articles had declarations
• N Engl J Med 1998338101-5

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Industry influence some solutions (2)

• Codes of conduct on gifts/relationships to drug
  reps e.g. AMA Council on Ethical Judicial
  Affairs
• Any gifts accepted by physicians individually
  should primarily entail a benefit to patients and
  should not be of substantial value
• Subsidies from industry should not be accepted
  directly or indirectly to pay for the costs of
  travel, lodging, or personal expenses of
  physicians who are attending conferences or
  meetings

44
Conclusions

• Industry influences medical publishing at all
  stages (funding, trial design, data analysis,
  publication, promotion of findings, ghostwriting)
• Influence goes largely undisclosed
• Industry influence arguably distorts the
  scientific record and distorts clinical medicine
• Disclosure is a partial panacea (we have a
  better chance of deciding for ourselves)

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A matter of life and death

• "The integrity of a body of literature is itself
  our society's ultimate temporal forum for
  negotiating life and death, suffering and
  wellness.....the medical well-being of the
  society it serves is dependent on the question of
  who stands behind the word."
• (Mark Gruber, anthropologist)