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The pharmaceutical industry’s influence on medical publishing. Gavin Yamey MD Deputy editor, wjm ( www.ewjm.com ) Assistant editor, BMJ (bmj.com). A question. You read a guideline by the AHA giving a “class I” recommendation for using tPA in acute stroke

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The pharmaceutical industry’s influence on medical publishing

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The pharmaceutical industry’s influence on medical publishing

Gavin Yamey MD

Deputy editor, wjm (www.ewjm.com)

Assistant editor, BMJ (bmj.com)


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?


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?


A question (3)

  • You’re 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 she’ll pay for you to go to a symposium.

  • What do you do?


What I’d like to talk about

  • Industry influence over clinical trials (funding, design, analysis, publication)

  • Reviews

  • Guidelines

  • Ghostwriting

  • Dissemination/promotion to physicians

  • Some solutions


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


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


Industry influence over clinical trials

  • Funding

  • Design

  • Data analysis

  • Publication


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 1986;1:155-8


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 1999;282:1453-1457


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 1998;338:101-106


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 2000;320:381


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 1998;159:1373-1374


Industry influence over trial design (2)

  • Using surrogate end points, and only publishing favorable ones

    Int J Technol Assess Health Care 1996;12:209-237


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 sponsor’s drug to be equal or better BUT in 48% of trials, the dose of the sponsor’s drug was higher

    Arch Intern Med 1994;154:157-163


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 1998;316:1935-1938


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 1997:277:1238-1243


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 2001;175:225-226


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 1998;159:955-957


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 1998;279:1566-70


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 2002;287:612-7


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?


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


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


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


A rarity?

  • No

  •  In one study, 19% of original articles surveyed had named authors who would not meet ICMJE criteria for authorship (JAMA 1998;280:222-224)

  •  11% had ghostwriters, who were not named as authors

  •  Reviews, editorials, clinical guidelines: higher prevalence?


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


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


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."


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“


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


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.


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. 2000;15: 478-483.


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 Jul;102(1):270-3


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 1988;26(12):1183-9


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 1994;272:355


Promotional material

  • Study of 106 statements made by drug reps during 13 presentations

  • 11% of statements were false, yet physicians rarely spotted them

  • JAMA 1995;273:1296-8


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


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


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.


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?


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 1998;338:101-5


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”


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)


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)


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