Scientific Research Today - Part II - Long

[Guest guest]

Part II of WA Monthly report by Shannon Brownlee.

 

Disheartened? Not furious? No, because DeAngelis could not know for

certain whether or not the authors held back half the data in order to

make their sponsor's drug look better " no matter how likely that

explanation may seem. When researchers submit papers to a journal, the

editor has little choice but to trust the authors have employed a

ruthless skepticism when viewing their own results, that they have

bent over backwards to minimize self-delusion. Editors and peer

reviewers can ferret out sloppy reasoning, look at how an author has

designed and executed a study, and correct faulty statistics, but as

Angell remarked, " We don't put bamboo slivers under their nails. If

they wanted to lie, they could lie. "

 

Articles of faith

 

Dr. Arnold Relman began worrying about this problem way back in 1977,

when he became editor-in-chief of The New England Journal. That year,

Relman got a call from a reporter about a paper that was due to appear

in the next issue, discussing serious side effects--including lowering

a man's testosterone and sperm counts--of a popular antacid. The

reporter wanted to know what Relman intended to do about the fact that

Wall Street analysts had acquired early copies of the paper and now

the stock of the company that made the drug was falling.

 

Relman, who began practicing medicine in the 1950s and calls himself a

" relic, " says before that reporter's call, it had never occurred to

him that medical research could have financial consequences for

industry. But the more he thought about it, he told me recently, " The

more I became convinced that the commercialization of medical practice

and medical research, and the use of the information for commercial

purposes, was a major threat to the integrity of the whole system. " He

recognized that medical researchers, being only human, would have

trouble applying that ruthless skepticism that was so necessary to

good science when there was money at stake.

 

The obvious solution to Relman and Angell, who was by then a deputy

editor at The New England Journal of Medicine, was disclosure. Forcing

authors to tell the world they were taking industry money, the editors

reasoned, would prompt a little soul-searching among researchers who

might otherwise be inclined to turn a blind eye to negative results or

shade conclusions in favor of a corporate sponsor. It would put them

on notice that readers would be watching. The editors also figured

that disclosure would help readers judge the validity of an author's

conclusions. " They could evaluate the data for themselves, " Relman

told me recently. " But the discussion, the interpretation by the

author can be slanted . . . it was still important for readers to know

when articles were sponsored by industry. " JAMA, largely at Rennie's

urging, followed suit soon after.

 

Six years later, Relman upped the ante by barring researchers with

conflicts of interest from writing editorials or review articles--like

the one penned in Nature Neuroscience by Charles Nemeroff " because they

carry great weight with doctors in private practice. Angell explains

their decision like this: " Imagine a judge who has before him a case

involving two companies suing each other--and he owns one of the

companies. And he says, 'Not to worry. I'm a judge and I learned how

to evaluate things in a dispassionate way.' He'd be laughed out of

court. " She and Relman argued that just as judges must recuse

themselves from cases in which they have financial ties to a litigant,

editorialists and review authors with conflicts of interest should

refrain from offering medical opinions.

 

Angell was still defending that decision a decade later, as editor in

chief at the Journal, when she wrote in 2000 that disclosure was not

sufficient to preserve the integrity of the science that appeared in

her journal's pages: " We believe that a policy of caveat emptor is not

enough for readers who depend on the opinion of editorialists. " Why

was it necessary to defend the Journal's policies? Partly because

authors were ignoring them. In 1997, when Sheldon Krimsky, a professor

of public policy at Tufts University, surveyed 61,134 articles in some

181 journals, he found that only 0.5 percent disclosed a conflict of

interest related to the topic of the article, an impossibly low number

given the fact that a quarter of biomedical researchers at the time

were receiving funding from industry. The reason for this low rate of

disclosure, as Krimsky notes dryly in his book, Science in the Private

Interest, is that " author compliance is not especially high. "

 

" Lots of eminent people took great offense at being accused of being

influenced, " Relman told me recently. " 'What an insulting thing to

say. I value my reputation; doctors and scientists know best. Trust

us.' I spent the first 25 years of my career doing clinical research

and being one of them, and I know the feeling. " As Harvey Lodish,

professor of biology at MIT, huffed to Technology Review in 1984, when

Relman first required disclosure at the Journal, " Scientists have all

kinds of private consulting arrangements with biotechnology companies

and many own stock in these companies, but that's nobody's business.

It has nothing to do with the quality of their research. "

 

" They actually believe that they aren't influenced, " says Angell.

Aside from the fact that it's not in physicians' self-interest to

acknowledge the effects of corporate money, they may have a hard time

seeing the problem for the same reason fish don't know they're

swimming in water: Doctors are surrounded by conflicts of interest

almost from the moment they arrive at medical school. Pharmaceutical

companies begin wooing young doctors with small tokens at first, pens

and coffee mugs emblazoned with drug logos, then escalating to pizza

night for medical residents, dinners at expensive restaurants and

tickets to sporting events. Most schools offer a class in medical

ethics, but there's no requirement that they discuss conflict of

interest. Besides, a few lectures can't outweigh the message young

doctors absorb every day, as they watch the icons in their

profession--their professors, visiting lecturers, heads of

departments--taking gifts, speaking on behalf of companies, flying

first-class to medical meetings in Paris and Honolulu. By the time

medical residents enter private practice or the lab, the gifts from

industry no longer seem like gifts, but entitlements " just another way

to be compensated for all those brutal, slogging years of lousy pay

and long nights.

 

A journalist friend of mine recently told me about the day his

then-girlfriend, who was a neurosurgeon, received a check for several

hundred dollars in the mail, along with a note from a drug company

representative. It seemed his girlfriend had made favorable mention of

a particular drug during a lecture she delivered a few days earlier,

and the money was just a little thank you from the manufacturer. When

my friend told her she could not in good conscience cash the

check--that it was a conflict of interest--she looked at him, he said,

as if he were speaking in some unintelligible language.

 

This deafness to the power of money to corrupt medical science leads

physicians and scientists to display an arrogance and a remarkable

naïvete, both of which were very much in evidence in a snippy

editorial entitled, " Avoid Financial 'Correctness,' " written in 1997

by the editors at Nature. They derided disclosure as a waste of time,

writing, " This journal will persist in its stubborn belief that the

research as we publish it is indeed research, not business. " The

Nemeroff case has not changed the editors' view substantially,

although they did alter their policy after it broke. Nature Publishing

now requires editorial and review writers, along with the authors of

original research papers, to inform readers whether or not they have

conflicts of interest, or to say they decline to declare. Charles

Jennings, executive editor of Nature, says they have no intention of

following the New England Journal in barring editorialists who have

conflicts. " I flatly disagree with that policy, " he told me. " That

would exclude many of the leading experts. You don't want a policy

that prevents Thomas Edison from writing about the future of

electricity. Our position is for readers to decide for themselves

about whether an author is biased. "

 

Of course, most readers, especially practicing physicians, don't have

the expertise or the resources to decide for themselves--to know how

the studies might have been constructed differently, whether the

conclusions have been shaded to favor the author's sponsor, or which

data the author decided conveniently to leave out of the article.

Knowing that an author might be biased doesn't aid in determining the

extent and nature of the bias. It's not as though there will be two

articles, one by a biased writer and one by an unbiased writer,

published side by side to allow readers to identify the differences.

Besides, conflicts of interest are now so pervasive, says Rennie, many

readers scarcely take note, even when they're disclosed.

 

Race for the cure?

 

It's tempting to wonder what medical research would look like if

universities and medical associations and editors of journals stopped

talking about how to manage conflict of interest and started thinking

about how to expunge it. Just say no. Proponents of Bayh-Dole will

object, claiming the pace of medical advances will slow to a crawl,

but bear with me for a moment and just imagine a different universe.

Let's start with the medical schools " those temples of higher learning.

They would be the first to cast out the drug merchants. Hospitals

would pay their medical residents a decent wage so they can afford to

buy their own beer and pizza. FDA advisory panelists who have a

financial stake in the drug being considered would not be allowed to

vote. And if the journals stopped publishing papers and editorials

penned by academic clinicians with conflicts of interest, authors

would be forced to choose between taking scientific credit and taking

the money.

 

Of course, that's not going to happen unless academic clinicians

somehow decide there's something wrong with the status quo. In Sheldon

Krimsky's view, the only way to deter conflict of interest is for

academics to feel shame. Maybe so, but as a journalist who has spent a

decade and a half peering at medicine from the outside, nose pressed

to the glass, I'm struck more than anything by the apparent lack of

shame among clinicians when it comes to this issue.

 

Here's a little thought experiment. Imagine that a medical

journalist " me, for instance " makes a tidy sum writing press releases

for, say Pfizer, the manufacturer of Viagra. I don't make a fortune,

maybe just enough to cover a year's tuition for my son's private high

school. And let's say for the sake of argument I also buy a few dozen

Pfizer shares. Then I turn around and write a story for The New York

Times about several new drugs for treating erectile dysfunction.

 

What would you think, dear reader, should my financial relationship

with the pharmaceutical company that makes one of the drugs featured

in my story come to light? Would you have reason to doubt its

objectivity and accuracy? Of course you would. Not only that, I would

be ashamed to show my face in any newsroom, and I would not be writing

for the Times again. I'm not trying to claim that journalists are

paragons of virtue, but we have no illusions about our ability to

withstand temptation and avoid shading what we say when faced with a

wad of cash.

 

Not so in medical research. In that world, the author of a review

article can have direct financial relationships with the manufacturers

of drugs he is critiquing and still argue he has done nothing

unsavory. What that suggests is a sense of fiduciary responsibility is

not built into the professional code of medicine, a doctor's internal

compass of right and wrong.

 

And of course there are also pecuniary reasons not to acknowledge the

power of money. The fact is, universities and doctors have become so

dependent on industry largesse they can't even imagine disentangling

themselves. Repeal the Bayh-Dole Act? Not on your life. Kick the drug

representatives who wheel their little carts filled with sample

packets of drugs out of your office? Who would pay for all those trips

to medical meetings in exotic locales?

 

Company line

 

And so they try to manage it. About half of universities require that

faculty disclose their conflicts of interest. A scant 19 percent set

limits on the outside financial interests faculty may hold. Harvard

University, long considered a paragon of scientific virtue, is now

considering relaxing its rules governing industry collaborations. Now

that Angell is gone, even the once-starchy New England Journal has

loosened its restrictions on editorialists and review writers, who are

now free to enjoy some corporate largesse, just not too much. " They

think it's possible to be virtuous and rich at the same time, to take

money from companies and then manage it, " says Angell. " They come up

with rules that are so complicated in order to give the appearance of

worrying about this, when what they are really worried about is the

money might go away. "

 

All their managing doesn't seem to be working, and we are the ones who

will suffer the consequences. In March 2000, the FDA yanked a diabetes

drug called Rezulin off the market after it had been linked to at

least 90 cases of liver failure and 63 deaths. The withdrawal came

three years after the agency had approved the drug to great fanfare.

Articles in the popular media quoted diabetes experts who praised

Rezulin, calling it " a truly novel approach, " and the manufacturer,

Warner-Lambert, enjoyed a spectacular 144 percent rise in its stock price.

 

By the fall of 1997, however, the FDA had already begun to receive

reports of patients on Rezulin suffering liver failure, a side-effect

that the agency's advisory panel glossed over during its

deliberations. A paper published in the New England Journal also made

scant reference to liver toxicity, saying the drug was " well

tolerated, and most adverse events were considered to be related to

the underlying diabetes. " Several clinicians with ties to the company

subsequently urged the FDA not to withdraw the drug, even as the body

count was rising. According to a Los Angeles Times investigation, at

least 12 of 22 scientists who played a central role in the

federally-funded study of Rezulin received research funding or other

compensation from Warner Lambert, while four of the 12 voting members

of the FDA advisory panel that approved Rezulin, and kept it on the

market an extra 30 months, had financial ties to the company.

 

When industry has penetrated every level of medicine from the lab

bench to the FDA advisory panels, from the pages of the medical

journals to your doctor's prescription pad, how are physicians to make

decisions about treating their patients? How are they to know whether

or not expensive calcium channel blockers are really better than

over-the-counter diuretics for high blood pressure? (They're not.)

Should you take a mildly depressed teenager to a psychotherapist, or

put him on an antidepressant and risk sending him into a suicidal

tailspin? Maybe a cholesterol-lowering statin drug will prevent this

patient from suffering a heart attack, as the studies claim. Then

again, maybe it will simply cause her muscles to break down and

destroy her kidneys, one of the drug's side effects.

 

And what about us patients? What are we to do with the knowledge that

much of what passes as science in medicine is little more than

gussied-up marketing? There isn't much we can do. And so, I say if

you're ill, if you are ailing, or just sick at heart, go find a doctor

who listens, who holds your hand. Just make sure you find a doctor who

looks at evidence, not opinion, and when she pulls out the

prescription pad, start asking a lot of questions.

 

Shannon Brownlee is a fellow at the New America Foundation.

 

 

 

 

 

 

[Guest guest]

Thanks Marcia.

 

It fits micely in the folder " medical scandals " that I

had just created in the Health, General folder.

Will read sometime at ease.

 

Ien in the Kootenays

*************************

" Never mind what the book says.

God gave you a brain. "

~A.T. Still, founder of Osteopathy

**************************