Flacking for Big Pharma: an article by Harriet Washington | The American Scholar

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Flacking for Big Pharma

Drugmakers don’t just compromise doctors; they also undermine top medical

journals and skew medical research

By Harriet Washington

“D

How can this be? Flimsy plastic pens that scream the virtues of Vioxx and

articles published in the pages of The New England Journal of Medicine would

seem to mark the two poles of medical influence. Scarcely any doctor admits to

being influenced by the former; every doctor boasts of being guided by the

latter. In fact, medical-journal articles are widely embraced as irreproachable

bastions of disinterested scientific evaluation and as antidotes to the long

fiscal arm of pharmaceutical-industry influence.



And yet, “All journals are bought—or at least cleverly used—by the

pharmaceutical industry,†says , former editor of the British

Medical Journal, who now sits on the board of Public Library of Science (PLoS),

a nonprofit open-access group publishing scientific journals that eschew

corporate financing and are freely available online to the public.

Big Pharma, as the top tier of the industry is known, starts modestly, inserting

the thin edge of its wedge by advertising copiously—and often

inaccurately—in medical journals. In 1981, concerned officials at the Food and

Drug Administration recognized the educational nature of pharmaceutical

advertising by establishing explicit standards for medical-journal ads that

mandate “true statements relating to side effects, contraindications, and

effectiveness,†and a “fair balance†of statements about medication risks

and benefits.

In 1992, the editors of the esteemed ls of Internal Medicine decided to

gauge how well their own advertisements met that standard. They tested 109

advertisements along with the references cited by those ads, sending each ad to

three expert reviewers who evaluated them in light of the FDA standards.

Fifty-seven percent of the ads were judged to have no educational value, 40

percent failed the fair-balance test, and 44 percent, the reviewers believed,

would result in improper prescribing. Overall, reviewers would have recommended

against publication of 28 percent of the advertisements, as the ls revealed

in its published report.

The FDA subsequently issued 88 letters accusing drug companies of advertising

violations between August 1997 and August 2002. But the ls editors were in

no position to bask in this validation: the journal was fighting for its life

after large pharmaceutical companies withdrew $1.5 million in advertising.

“Finally, the editors felt that to save the journal, they must resign,â€

recalls . The coeditor of the ls, Fletcher, remarked as he

departed his job: “The pharmaceutical industry showed us that the advertising

dollar could be a two-edged sword, a carrot or a stick. If you ever wondered

whether they play hardball, that was a pretty good demonstration that they

do.â€

A decade later, with a different editor at the helm and a restored

pharmaceutical advertising base, the ls planned an editorial on high drug

prices. But this time, it took care to first invite commentary from the premier

drugmakers’ organization, the Pharmaceutical Research and Manufacturers of

America (PhRMA). PhRMA in turn funded a piece by E. Calfee of the American

Enterprise Institute, whose essay began with the statement “Price controls

could have a substantial negative effect on pharmaceutical research and

development.â€

Pharmaceutical advertising impinges heavily on the editorial sphere of medical

journals, sometimes with surprising brazenness. The drug epoetin is widely

accepted for its role in prolonging survival in people with end-stage renal

disease: Medicare alone spent $7.5 billion on the drug in the decade preceding

2002. Dennis Cotter is president of a nonprofit institute that scrutinizes

conventional medical wisdom, and his group’s analysis suggested that

epoetin’s benefits for people with end-stage renal disease were largely

chimerical, based on flawed logic. In 2003, Cotter submitted an editorial that

detailed his questioning of epoetin’s role to Transplantation and Dialysis,

whose editor and peer reviewers agreed that it should be published. However, as

the British Medical Journal reported in January 2004, ph Herman,

Transplantation and Dialysis’s editor, rejected the piece because

“unfortunately, I have been overruled by our marketing department with regard

to publishing your editorial. The publication of your editorial would, in fact,

not be accepted in some quarters . . . and apparently went beyond what our

marketing department was willing to accommodate.â€

After a hue and cry was raised in the medical press, the journal reversed itself

and offered to publish Cotter’s work, but he demurred, preferring a less

commercial venue.

Medical journals are utterly dependent upon pharmaceutical advertising, which

can provide between 97 and 99 percent of their advertising revenue. By 2005,

some major journals, including Consultant, Geriatrics, and American Family

Physician, carried more advertising than editorial pages and glossy, full-color

inserts that were longer than the journal’s longest article. This explains why

medical journals themselves advertise to drugmakers, flooding the pages of

pharmaceutical-industry publications such as Medical Marketing and Media to vie

for the attentions of Big Pharma. The Journal of the American Medical

Association (JAMA) bills itself in advertising as “a priceless audience at a

price you can afford,†while the ls boasts: “With an audience of more

than 90,000 internists (93 percent of whom are actively practicing physicians),

ls has always been a smart buy.â€

Moreover, drugmakers sometimes agree to buy journal advertising only if it is

accompanied by favorable editorial mentions of their products. Or their in-house

stables of writers or hired pens generate “advertorials,†a ensteinian

mix of medical content and marketing messages that can be indistinguishable from

editorial material. “Pharmaceutical firms also inform journals,â€

observes, “that they are receptive to buying huge volumes of reprints that

favor their wares: The profits for the journal can easily reach $100,000.â€

Pharma’s journal ads tout not only products but also its hundreds of thousands

of subsidized “educational opportunities.†Drug and medical-device makers

spend $2 billion annually for more than 300,000 seminars and training

opportunities, often held in the Bahamas or the Caribbean. The wolfed-on-the-run

free pizza for harried medical residents that the industry has so

sanctimoniously forsworn bears little resemblance to the sumptuous feasts,

flowing wines, chartered flights, cruises, luxurious lodgings, golfing,

snorkeling, and remarkably attractive sales reps that characterize these island

educational junkets.

“There’s a lot of bribery involved—the kids get pizza, the grownups get

trips to Hawaii,†observed Marcia Angell, MD, professor of social medicine at

the Harvard Medical School, former editor-in-chief of the New England Journal of

Medicine (NEJM), and the author in 2004 of The Truth About the Drug Companies:

How They Deceive Us and What to Do About It.

These pedagogic playdates familiarize doctors with pharmaceutical companies’

patented products to the exclusion of cheaper and sometimes safer and more

effective alternatives. By 2000, drugmakers were paying physicians a total of $6

billion a year for trinkets, island “educational opportunities,†and

financial grants for their pet projects, from golfing jaunts to clinics; this

doesn’t include the speaking and consulting fees that the pharmaceutical

industry pays influential and “high-prescribing†clinicians to discuss its

products. “Drug companies have moved their gift-giving from drug reps to

hiring ‘thought leaders’—the best drug reps of all,†says Angell.

“They send experienced physicians out to give talks and ensconce them on

well-paid speakers’ bureaus. Then they claim that this is education, not

marketing.â€

However, the industry’s seduction doesn’t end with the advertisements,

junkets, and overpaid speaking engagements. Drugmakers have enticed or ensnared

the very font of evidence-based medical knowledge—the peer-reviewed medical

journal. Not content to turn these journals out to ply the streets for cash, the

industry finds many ways to pervert the editorial content itself.

his perversion is such an open secret that in 2003 the British Medical

Journal published a tongue-in-cheek essay instructing researchers in the fine

art of “HARLOT—How to Achieve positive Results without actually Lying to

Overcome the Truth.†L. Sackett, director of Ontario’s Trout Research

and Education Center, and D. Oxman, director of the Department of Health

Services Research at Norway’s Directorate for Health and Social Welfare,

wittily summarized strategies by which drugmakers use clinical trials to tart up

drugs that are poorly performing, dangerous, or both.

The proper conduct of a research study requires that it pose an important

medical question in a clear, unambiguous manner and that it is carefully planned

and randomized to ensure that the results are accurate and broadly applicable.

Large numbers of subjects are typically recruited to help ensure that the

results do not arise by chance. Control groups are given placebos or the

standard of care in order to allow a meaningful comparison with the study group.

Statistical expertise helps the study designers minimize and tease out any

sources of error or bias.

But this expertise can also be used to introduce intentional bias in order to

attain the desired result: for the determined adept, there exist many ways to

subvert the clinical-trial process for marketing purposes, and the

pharmaceutical industry seems to have found them all.

HARLOT’s advice to those who would serve Pharma includes, “test against

placebo, test against minimal dose, test against maximal dose, and test in very

small groups.†This means that companies sometimes seek to make bad drugs look

good by:

Comparing their drug to a placebo. A placebo, such as a sham or “sugarâ€

pill, has no active ingredient, and, although placebos may evoke some poorly

understood medical benefits, called the “placebo effect,†they are weak:

medications tend to outperform placebos. Placebo studies are not ethical when a

treatment already exists for a disorder, because it means that some in the study

go untreated. However, if you care only that your new drug shines in print,

testing against placebo is the way to go.

Comparing their drug to a competitor’s medication in the wrong strength. Too

low a dose makes the rival drug look ineffective. Too high a dose tends to

elicit worrisome side effects.

Pairing their drug with one that is known to work well. This can hide the fact

that a tested medication is weak or ineffective.

Truncating a trial. Drugmakers sometimes end a clinical trial when they have

reason to believe that it is about to reveal widespread side effects or a lack

of effectiveness—or when they see other clues that the trial is going south.

Testing in very small groups. Drug-funded researchers also conduct trials that

are too small to show differences between competitor drugs. Or they use multiple

endpoints, then selectively publish only those that give favorable results, or

they “cherry-pick†positive-sounding results from multicenter trials.

An increasingly popular variant is the much-abused technique of “data

mining,†wherein small subgroups of an unsuccessful trial are relentlessly

scrutinized in search of groups for whom a benefit emerges, or seems to.

When he sought a novel way to focus attention on the frequently deceptive nature

of data mining, Dr. Sleight, professor of cardiovascular medicine at

Oxford University, might have been guided by Molière’s advice: “One easily

bears moral reproof, but never mockery.†Accordingly, in lieu of ethical

finger wagging, Sleight illuminated the dangers of data mining by using mockery,

stratifying some drugs’ effectiveness by astrological sign. In 1988, he and

his team analyzed the data of the International Study of Infarct Survival

(ISIS-2), a real, 17,000-person clinical trial in the United Kingdom that asked

whether aspirin helped people who had suffered a recent heart attack. This study

found that the beneficial effect of aspirin for patients having a heart attack

was quite as powerful as that of streptokinase, another effective

clot-dissolving medication.

But when Sleight sorted the patients’ responses by astrological subgroup,

taking aspirin was associated with a good outcome for all birth signs except for

Libra and Gemini, who were more likely to die when given aspirin. In 1985,

another large study, ISIS-1, had found a 71 percent reduction in the death rate

of people born between July 24 and August 23 (Leos), who took the beta-blocker

atenolol, as compared to people of all other birth signs, who enjoyed a

mortality reduction of only 24 percent. Sleight concluded with this warning:

“When in a trial with a clearly positive overall result, many subgroup

analyses are considered, false negative results in some particular subgroups

must be expected.â€

In 2005, BiDil, a congestive heart-failure medication, became the first

FDA-approved drug for African Americans only. BiDil was not tailored for African

Americans, as its proponents often claim, but began life as the only patented

drug of the Lexington, Massachusetts, biotech firm NitroMed. In 1987, the FDA

had rejected NitroMed’s application based on feeble results in its clinical

trials, but the company scrutinized the drug’s data in search of some group

where it might show efficacy. Peering into BiDil’s efficacy in women and in

other subgroups yielded no fruit, but before NitroMed had to resort to

astrology, the NIH passed the FDA Modernization Act, an initiative for the

inclusion of racial minorities in clinical trials. NitroMed suddenly detected

evidence in the FDA-rejected 1980s data that its drug might work better for

blacks than it had for whites, and in 1997 BiDil was reborn as a “blackâ€

drug.

BiDil proponents published studies that supported their claim of a racially

mediated genetic anomaly that was addressed by BiDil, making it an ideal drug

for blacks but not for whites. At the company’s invitation, other physicians

published papers arguing for this genetic racial difference, but they could do

so only by giving short shrift to critically important environmental and

behavioral differences between black and white patients, such as disparate

diets, smoking rates, environmental exposures, and exercise levels. NitroMed won

FDA approval of a new trial that included only 1,050 black subjects, with no

white subjects to provide comparison data. Furthermore, BiDil was not tested

alone, but only in concert with heart medications that are already known to

work, such as diuretics, beta-blockers, and angiotensin-converting enzyme (or

ACE) inhibitors. The published results of the trial were heralded as a success

when subjects taking the drug combinations that included BiDil enjoyed 43

percent fewer heart-failure deaths.

The zealous data mining and the pairing of BiDil with drugs that are known to

work well are recognizable tenets of HARLOT. Moreover, excluding whites was a

medically illogical but financially strategic move because it eliminated the

possibility that the drug would test well in whites, thereby robbing NitroMed of

its already thin rationale for calling BiDil a black drug. The “black†label

was crucial, because BiDil’s patent covering use in all ethnic groups expired

in 2007, but the patent for blacks only allows NitroMed to profit from it until

2020. BiDil is a case study in research methodology “flaws†that mask

strategies calculated to make a dodgy drug look good on paper, for profit.

he medical record is also effectively distorted through what is not said,

suggests Marcia Angell. “Any reputable journal is at the mercy of what is

submitted to it,†she says, “and must choose from whatever comes over the

transom. Many studies never see the light of day because their findings are

negative. There is a heavy bias toward positive studies, and this negative bias

is a real problem... " More at link...

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