Boston Magazine: A Prescription for Trouble: When NEJM gets something wrong

[Guest guest]

A Prescription for Trouble

Its reports on new drugs put billions in pharmaceutical company profits and

untold lives at stake. So it’s a very big deal when the New England Journal

of Medicine gets something wrong. With the powerful publication still reeling

from a scandal it can’t seem to shake, editor Drazen’s plan for

fixing things is less a sure-fire cure than a leap of faith.

By Donovan

Editor Drazen believes the Journal was " hoodwinked " by the authors

of its infamous Vioxx study. Photo by Mark Ostow.

For guests staying at the Cleveland InterContinental Hotel, late-night trips

to the ice machine can be quite an adventure. The hotel is connected, via a

short walkway, to the Cleveland Clinic, one of the country’s busiest

hospitals; make a wrong turn, and the décor shifts abruptly from faux Chinese

vases

and dark wood paneling to bright fluorescent lights, swinging metal doors, and

nurses’ scrubs. So when the InterCon played host this September to a

conference on the blurring line between medicine and commerce, it seemed the

organizers could not have chosen a more fitting venue.

With endocrinologists and anesthesiologists toiling almost within earshot,

the 300 prominent doctors, lawyers, and academics who’d turned out for the

event nibbled hors d’oeuvres and talked shop outside the hotel’s ballroom.

Thornburgh, the former U.S. attorney general, gave the lunchtime

address.

Nina Totenberg, legal affairs correspondent for NPR, moderated a session. The

main attraction, though, was conspicuously absent. Word was spreading that

Drazen, the powerful editor in chief of the New England Journal of

Medicine—and the featured dinner speaker—was stranded in Boston, his flight

out of Logan delayed by steady rain in northern Ohio.

There can be few people more qualified than Drazen to address the subject of

conflicts of interest in medical research. And there can be few people for

whom the subject is as acutely uncomfortable. (It is easy to imagine Drazen,

back in the Logan departure lounge, doing a little rain dance.) Since November

2000, when the Journal published what it later acknowledged to be a flawed

study on Vioxx, a new painkiller from the pharmaceutical giant Merck, pointed

questions about how the study made it into the world’s most influential

medical journal, and about the journal’s response to the controversy, have

dogged

Drazen wherever he goes.

The circumstances surrounding the Vioxx affair are complex, and some of them

still in dispute. The now infamous study, which touted the new drug’s

benefits—it caused fewer stomach problems than naproxen, an older painkiller

marketed as Aleve—also significantly understated its health risks: Namely,

three

more Vioxx patients had heart attacks than were reported, and another 47

experienced serious cardiac problems. These particular details didn’t emerge

until

Merck submitted testing data to the Food and Drug Administration. In the

meantime, 900,000 glossy reprints of the article—which Merck purchased from

the

Journal for as much as $836,000—were on their way into the hands of doctors

around the country. Some 20 million Americans took the potentially dangerous

drug before it was withdrawn from the market in 2004.

To make matters worse, two of the study’s 13 authors were Merck employees.

The Journal is by no means the only periodical of its kind to have faced

accusations of conflict of interest, or to have published flawed data. But the

Vioxx study, in combining both indiscretions, looked less like oversight than

something far more pernicious. Journalists, sensing a how-the-mighty-have-fallen

scenario, have covered the incident with gusto. Trial lawyers have also

smelled blood: More than 14,000 lawsuits have reportedly been filed against

Merck

over the Vioxx affair, further entangling the New England Journal in the

mess.

Last December—five years after the fact—the Journal finally took a stab at

damage control, publishing an unusual “Expression of Concern†claiming its

editors had “recently obtained information†about the three unreported heart

attacks that had resulted in a “misleading conclusion†about the risks of

Vioxx in the published paper. Drazen said he had been spurred into action when

the Journal became aware of an internal memo from Merck revealing the company

had tabulated the heart risks well before the Vioxx paper was published. The

“Expression of Concern,†Drazen said, was intended to “show the world that

we will not tolerate this type of behavior!â€

The Wall Street Journal, for one, was underwhelmed by Drazen’s newfound

indignation. It argued that the response was little more than an attempt to

insulate the magazine from executive editor Curfman’s admission, in a

videotaped deposition, that the New England Journal had been guilty of “lax

editing†on the Vioxx study. The article further implied that the journal’s

belated retraction may have put lives at risk: “Had the journal acted before

the

recall, its authoritative voice almost certainly would have damped the Vioxx

boom.†Merck, meanwhile, responded to the New England Journal’s claims with

a

vigorous denial, stating that it had completely followed the publication’s

own rules, a rebuttal that received extensive coverage. This August the

Journal of the Royal Society of Medicine, a British publication, concluded that

“

the New England Journal of Medicine, and medical journals in general, have been

damaged.†Rather than mitigate the controversy, Drazen’s actions only

invigorated it.

Not surprisingly, the ongoing Vioxx imbroglio has driven the Journal into a

permanent defensive crouch. For weeks I’d been involved in an elaborate game

of cat-and-mouse with Drazen’s PR reps, trying to set up an interview. So

when Drazen finally arrived at the conference, I decided to just walk over and

introduce myself. After a half-hearted handshake and an awkward silence, he

launched into a discussion about his son, who lives in Oslo and is studying

something called large-scale turbulence. It was his way of making small talk.

Drazen, who was a renowned asthma researcher before taking the job as the

Journal’s top editor in 2000, never strays far from the details of science.

As

we chatted, though, it was his bow tie that I kept thinking about. It bore

the New England Journal of Medicine logo, a maroon seal showing a quill pen

crossed with the snake-entwined staff of Asclepius, the god of medicine.

“It’s

a limited edition,†Drazen said, not really looking at me. I kept staring.

This was no ordinary bow tie, not one of those clip-ons worn by gawky teenagers

at their proms. A perfect ribbon, it seemed as inviolable as the fondant

frosting on a wedding cake. “Did you do that yourself?†I asked. He said it

was

as simple as tying his shoes. Apparently moved to prove it, he tugged on the

ends of the tie, unraveling it. Then, without looking down, he quickly

remade the bow. This version, alas, was less immaculate than the original.

To Drazen, critics who suggest that the New England Journal was asleep at

the switch when it let the Vioxx study into its august pages have

misrepresented the role that medical journals play. To be sure, they take

measures to

safeguard the quality of their material—when manuscripts come in, they are

subjected to peer review, in which experts evaluate them for accuracy,

originality,

and scientific significance—but beyond that, the argument goes, there’s not

much the journals can do to ensure they get all the details perfect. In a

letter to the Wall Street Journal objecting to its reporting on the Vioxx

controversy, Drazen pointed out that “editors have no subpoena powers.†The

medical journals are just a bridge between researchers and doctors; the real

responsibility for a study’s findings lies with its authors. And that,

basically,

was the message he was about to deliver to his colleagues in Cleveland as

they started in on their filet mignon dinners.

Taking the dais, Drazen warmed up his audience by telling them he had enjoyed

the spinach salad—a good way, he quipped, of getting more people into the

ICU. It took him more than 30 minutes, as diners moved on to the tiramisu, to

get to his own involvement in the Vioxx debacle, which had been limited to its

aftermath. During his earlier career as an asthma researcher, he had

partnered with as many as 21 pharmaceutical companies—ties that led some to

question

whether he could remain impartial as editor of a medical journal. To quell

that criticism, Drazen had sold his drug company stock, ended his consulting

arrangements, and agreed to refrain from working on articles involving any of

those companies for two years. As it happened, one of the companies he’d had

ties to was Merck. Before an issue is sent out the door, the Journal’s

editors use different-colored pens to make their final changes. (Drazen uses

purple

—“the royal purple,†he says.) It had been Curfman, the executive editor,

who’d signed off on the Vioxx study with his green stroke.

Facing the Cleveland crowd, Drazen invoked Kierkegaard, the Danish

philosopher who wrote that life must always be lived forward, but appreciated

backward. Then he compared himself to Grady Little, at the moment Little chose

not to

pull Pedro ez in the seventh game of the Sox’s 2003 pennant series

with the Yankees—a roundabout way of saying that hindsight is 20/20. Yes, he

said, he could have gone back to the Vioxx authors and asked them to explain the

discrepancies between their paper and the data that later appeared on the FDA’

s website. But the word “on the street†was that the FDA numbers were

“late

dataâ€â€”industry-speak for results that come in after a study’s formal

cutoff. In other words, he had given the authors the benefit of the doubt,

assuming

they’d filed incomplete information because they themselves simply didn’t

have all the facts yet. “The study was done in 22 countries,†he said.

“They

probably had case reports in Swahili, and they had [to get] them translated

and collated and gotten in.â€

The Journal, Drazen now believes, “had been hoodwinked.†But he doesn’t

see

that as cause for an overhaul of his organization; instead, his approach is

to depend on contributors to just play fair—a high-stakes wager on a system

that many, even inside the industry, see as being in need of repair. “

[Medical] journals have become an extension of the marketing arm of the

pharmaceutical industry,†says , ex-editor of the British

Medical Journal and

author of The Trouble with Medical Journals. “And the industry generally

gets the results it wants.â€

The studies these journals publish tend to be funded by drug companies, which

is sort of like Merrill Lynch paying for the content of Barron’s. And the

authors of the studies are often bound by contract to get verification of the

relevant data from the sponsoring company. This process inevitably creates

potential for the company in question to offer a few helpful pointers on how the

data might be interpreted. “That’s the rub right there,†says Dr.

Topol, a cardiologist and one of the earliest critics of Vioxx. “Because the

company might want to position things—spin, if you will—in a more positive

light

for their drug.â€

Indeed, a good review in the Journal is to a new drug what Ebert’s

upturned thumb is to a new movie—a stamp of quality that can translate into

huge

profits. “For them to have reprints from the New England Journal, that gives

them the seal of approval that this is good stuff,†says Topol. “And that

gets them into doctors’ offices.â€

The Journal has earned its unmatched credibility over the course of almost

two centuries. But in recent decades, that reputation has become increasingly

fragile. Drazen isn’t the first editor to face threats to its

integrity—both

from outside and within its own walls.

Though most Bostonians have never laid eyes on a copy of the New England

Journal of Medicine, the publication is part of our figurative landscape, one

of

the institutions that foster our city’s sense of intellectual superiority.

Published on Thursdays, it goes out to more than 180,000 print subscribers,

about 85 percent of whom are physicians, and about 13,000 more online. Even if

you don’t read it, you know its name: No other research journal, anywhere, is

cited as much. The Journal’s very appearance projects an aura of gravitas:

Its cover consists of nothing more than an index of its featured articles,

which include both research studies and “editorials,†in which contributors

comment upon issues relating to medicine and research.

Founded in 1812, the New England Journal is the oldest continuously

published periodical of its kind in the world. It’s owned by the Massachusetts

Medical Society, which bought it for a dollar in 1921. Behind these quaint,

dignified, so-very-Boston details, though, there is another story, one of an

ongoing

tension between the commercial interests of the magazine and its role as a

stolid, unimpeachable medium of medical news and analysis. Such is its clout

that the outcome of this struggle will have significant implications for

medical journals worldwide.

The Journal’s rise to eminence began in earnest in 1967, with the editor Dr.

Franz Ingelfinger, who had a knack for convincing top researchers to place

their best studies with him. It was under Ingelfinger’s reign, too, that the

Journal began to operate more like a traditional news outlet than a branch of

the medical community. In 1969, he instituted what remains known as the

Ingelfinger Rule, refusing to run studies that had been published or even

touched

upon elsewhere—a medical man by training, he was also a canny magazine editor

who knew the value of a scoop. Circulation rose rapidly during the

Ingelfinger years, as well as the Journal’s international prestige, but that

growth

came with risks. While heightening the impact of New England Journal articles,

Ingelfinger’s strategy also increased its vulnerability when one of those

articles proved tainted. (If, say, you run an exclusive study featuring an

anti-acne medication that later causes people’s teeth to fall out, you’re

the one

left holding the teeth.)

A gastroenterologist, Ingelfinger diagnosed his own esophageal cancer and in

the mid-1970s was forced to retire. He recommended as successor his close

friend Dr. Arnold S. Relman, a professor at Boston University’s medical

school

and former chief of medicine at Boston City Hospital, who was given the job in

1977. Where Ingelfinger had succeeded in generating buzz, Relman’s legacy

would be safeguarding the Journal’s integrity. In 1984, he made it the first

medical journal to require authors to disclose their financial ties to

companies they wrote about. Later, he went a step further, enjoining

contributors

from reviewing drugs produced by companies to which they had ties.

At the same time Relman was tightening the screws, the pharmaceutical

industry began to step up its marketing efforts, with the Journal reaping some

of

the benefits. This sudden infusion of money would do more to change the

culture and the content of the Journal than any amount of editorial rules and

regulations.

When Relman began as editor, the Journal maintained its own bank account and

kept its own books, and at the end of each year would submit a financial

statement to the Massachusetts Medical Society, along with a portion of its

income. “It was all kind of friendly and low-key,†he says. “We weren’t

talking

about a lot of money.†With profits topping off at $1 million in a good

year, according to Relman, the Journal had yet to become the cash cow it is

today

(the Journal made $88 million last year, $20 million from advertising). But

it was headed in that direction.

Relman floated the idea of using the extra cash to establish a trust fund for

research and education. Instead, he says, the Medical Society decided to

combine the Journal’s bank account with its own. “I objected to it as

strenuously as I could,†he says, recalling his admonition to the trustees:

“Don’t

allow the Society to live off the Journal, because sooner or later, that will

compromise its integrity.†His plea, he says, “didn’t cut any ice at

all.â€

(According to communications director Fortin, the Medical Society

created investment accounts that were “in the spirit†of Relman’s

proposal.

Whatever funds aren’t plowed back into the Journal, he says, “go toward

advancing

medical knowledge, and advocating for patients and physicians.â€)

After 14 years at the helm, Relman left the Journal in 1991. It was a tough

job, he says, and he was tired. But there was also a sense that he’d become

too keen to tackle the issue of money in medical research, a claim Fortin

denies: “No one here shies away from controversy.†The search committee

charged

with finding the next editor tapped Jerome P. Kassirer, a professor at the

Tufts School of Medicine. Kassirer kept Relman’s tough conflict-of-interest

policies in place, and by 1996 the Journal still stood alone in barring authors

from penning editorials about companies in which they have a financial

interest.

Despite the efforts to keep its content uncompromised, the New England

Journal, like all medical journals, was vulnerable to self-interested

contributors. During the same year its strict standards put it in the vanguard

of the

industry, the Journal somehow allowed itself to be duped by the authors of an

editorial that touted the diet drug Redux. A published study had shown that the

drug posed a significant risk for hypertension, but the Journal piece

concluded that any risks were outweighed by its benefits. It turned out that

the

authors had been paid consultants for companies that manufactured or marketed

the drug.

Kassirer learned about this the hard way. Newspaper reporters, who had

received advance copies of the article, called the Journal’s offices asking

about

the conflicts of interest three days before the August 29, 1996, publication

date. The authors had received the magazine’s standard letter, which warned

editorialists that they could not have “regular†consultancies or

“ongoingâ€

financial relationships with their subjects, and they had written back

stating that they had no such ties. The New England Journal later published an

editorial on the sorry episode, and tightened the phrasing of its policy to

make

it less open to interpretation.

Even as the Redux fiasco played out, though, the Medical Society began to

push its prized publication to be less picky about the articles it published,

and to extend its brand to other titles, a move many of its editors saw as a

blatant moneymaking scheme. One Medical Society consultant pointed out that the

Journal published just 10 percent of the manuscripts it received, and

asked, “Why should we let this meat fly out the door?†Line extensions were

proposed—the New England Journal of Cardiology, the New England Journal of

Oncology

—to be filled with articles deemed not worthy of the main journal itself.

The editors had another name for these proposed publications: the New England

Journal of Rejects.

The Journal’s editorial offices are on the sixth floor of the Francis A.

Countway Library, at the Harvard Medical School near Brigham Circle. The

setting

provides editorial staff with a psychological barrier—and geographical

distance—from the Society suits, who operate out of a lavish, modern

three-story

building in a corporate office park in suburban Waltham. Two ponds grace the

manicured grounds. Inside, an atrium towers overhead. The Journal’s editors

call it the “Taj Mahal.â€

Since before Kassirer’s term as editor, the Medical Society had been pushing

to relocate the Journal’s editorial offices to the compound. Kassirer

resisted the move. “I thought it was a really bad idea to have members of the

Medical Society able to walk into the editorial offices of the Journal,†he

says. “

The big advantage to the Countway Library is that you can’t park around it.

You can’t park, and nobody ever showed up there.â€

Kassirer and other editors saw the proposed move as another step toward the

commercialization of their enterprise, an undermining of the divide between

business and editorial. Kassirer recalls, for instance, how the Medical Society

zeroed in on the revenue-generating potential of the Journal’s newly

created Web page, back in 1996. “They were talking about a lot of advertising

on

the Web page and [posting] content that wasn’t the New England

Journal’s,†he

says. “I had no authority over these decisions, because the Medical Society

owns the Journal, and I was just the editor in chief.â€

Kassirer took the spat public in 1998, penning a report headlined “A Higher

Calling.†He reprinted the Journal’s own mission statement, which speaks of

advancing medical knowledge and developing professional and ethical

standards, but nowhere mentions maximizing profits. “Does the Society want to

become a

business?†he wrote—a controversial question considering the Medical

Society is a nonprofit organization. A year later, Kassirer was gone.

Marcia Angell, then the executive editor, succeeded Kassirer as editor in

chief. Already, Angell was well acquainted with the Society’s quest to

capitalize on the Journal brand. “Titles got more and more grandiose,†she

says, “

until it sounded like something out of Gilbert and Sullivan.†Angell, too,

ran

afoul of her bosses. At one point, she says, Jack Evjy, president of the

Medical Society at the time, asked her, “Marcia, what do you have against

money?â€

She kept her job for less than a year. “They hated her as much as they

hated me,†Kassirer says.

In Angell’s farewell editorial on June 29, 2000, she wrote that “the

Journal is no longer an independent entity, but part of a larger enterprise.â€

Today, she says, the same thing holds true. “There’s nothing like money to

make

people want more of it.â€

Six years into Drazen’s tenure as editor of the New England Journal,

the dreaded move to Waltham has yet to happen. From his office, Drazen can

still look across the street to the Brigham and Women’s Hospital, where he

used to be chief of pulmonary and critical care medicine.

One morning, I meet with Drazen in his office. Bald and bespectacled, he

carries himself stiffly, and rarely makes eye contact. Sitting behind his desk,

in his chestnut-brown cardigan sweater and bow tie—this one polka-dotted—the

60-year-old looks very much the academic. The most notable thing about his

office, meanwhile, is the abundance of grandfather clocks. There are lots of

them, here and at his home in Winchester. He restores them, he explains, in his

basement. A tinkerer by nature, Drazen studied engineering and physics as an

undergraduate at Tufts University. “I grew up wanting to do research,†he

says.

At Harvard Medical School, his very first patient was a 14-year-old girl from

Peabody who was suffering from asthma. At the time, there weren’t any good

treatments available to control the disease. So Drazen set out to create one.

Years later, as he and his colleagues completed a trial on a treatment for

bronchoconstriction, competing researchers stole their thunder, publishing the

results of a similar trial in the British medical journal the Lancet. Drazen

had been in a race for scientific discovery, and he had lost. Eventually, he

and his team contributed to the creation of three widely used asthma

treatments—Accolate, Zyflo, and Singulair—but the episode left its mark.

Certainly

it gave Drazen a keen sense of the competitive, first-past-the-post nature of

medical research, a sense he carries with him to this day.

Before he became editor, there were complaints that the Journal was too

focused on general-interest health issues, that the research end of things got

short shrift. Immediately, Drazen set out to change this. He would publish more

clinical drug trials—trials like the Vioxx study—rather than surveys of

people’s habits, the kind that gauge, say, the health effects of eating

chocolate or drinking red wine. The Vioxx affair, however, suggested that Drazen

may

have tilted things a little too far in the other direction, allowing his

sympathy for his fellow researchers to cloud his judgment. He says, for

instance,

that one reason he waited so long to disavow the Vioxx study was that he didn

’t want to damage the careers of the study’s authors.

Drazen’s tenure at the New England Journal has also been marked by a

vigorous dedication to making its content timely. In 2003, for instance, he saw

to

it that the Journal was at the forefront of reporting on the SARS virus,

publishing detailed case studies of the disease within two and a half weeks of

the

World Health Organization’s public advisory. In this regard, even the Vioxx

study provides Drazen with a measure of satisfaction. While the Journal may

not have provided a complete account of the coronary risks of the drug, he

points out, it did at least report on some of its risks before other journals.

“

It was the first!†he says.

Even as the Vioxx controversy drags on, Drazen insists he has maintained a

good relationship with the people at the Society. “It was a risk, when I took

the job, that I could have been put in a position where I was being controlled,

†he says, “but what’s happened is exactly the opposite. I’ve been

given

the resources I need to do what I wanted to do, and the Medical Society has

pretty much otherwise left us alone.â€

But Drazen hasn’t exactly been spoiling for a fight, either. Like his

predecessors, he believes the Journal’s most precious asset is its name.

“It would

be foolish to squander that,†he says, “to make a few bucks.†And yet, he

adds, “I’m a believer that if you don’t have a margin, you can’t have a

mission. We’re not a charity.†While the deal Drazen cut with the Society

required his approval of any use of the Journal’s name on publications, he is

by no

means a stickler when it comes to extending the brand. “I was willing to try

new stuff,†he says. When Drazen arrived, the Journal was still working with

old-fashioned paper manuscripts. Today it has podcasts. He still meets

regularly with Society members to discuss further improvements. “You

couldn’t

have a wall between you and the publisher about every single issue,†he says.

Most remarkably, perhaps, Drazen has relaxed the Journal’s long-standing

conflict-of-interest policies. Today the publication merely requires that

editorialists have no “significant†financial interests with the drug

companies

being written about, meaning $10,000 or more. “The problem is that it’s

difficult to define zero,†he explains. “Do you count a pen? A mousepad? An

educational grant?â€

While some would argue that Drazen’s shift risks the Journal’s getting too

cozy with drug companies, others would say it’s not cozy enough. Dr.

Stossel—a professor at Harvard Medical School, senior physician at Brigham and

Women’s, and the brother of 20/20 correspondent Stossel—is one of

these people. Stossel believes that the “Expression of Concern†Drazen

published

overstepped his duties. “In my opinion, there’s no smoking gun to show that

Merck deliberately misled anyone,†he says, adding, “To the extent that it

hurts Merck, it hurts us all. Merck has no obligation to make drugs, and if

tomorrow they decide it’s safer and more profitable to make dog food,

they’ll

do it.â€

Stossel’s criticism points to an inevitable occupational hazard for someone

in Drazen’s position: No matter what you do, someone’s going to think it’s

the wrong course. But the embattled editor shows no signs of cracking just yet.

Recently, he told a reporter that he intends to stay at the Journal until

2012, when it will celebrate its 200th anniversary. Perhaps by then the memory

of the Vioxx scandal will have faded, and come to be regarded as what

President Bush might call “just a comma.â€

When I ask exactly what has changed in the wake of the Vioxx mess, and what

he’s doing to make sure it doesn’t happen again, Drazen tells his assistant

to print “The Paragraph.†In an instant, the piece of paper sits on the

table

before me: “Our expectation is that your revised manuscript will include

full, accurate, and up-to-date reporting of adverse events. In general, this

should include a table containing descriptions of all serious adverse events

and

all common or important other adverse events. We believe it is important

that the abstract contain a statement regarding adverse events.â€

Drazen says his editors are being “a lot more cynical†with authors and

asking a lot more questions about the harmful side effects of drugs, “almost

to

the point of driving them nuts.†And that’s it. In the thick of a scandal

involving his journal’s being “hoodwinked†into publishing a dubious

study, in

the midst of a financial boom in the medical research industry that has

intensified competition to a mind-boggling degree, the editor has chosen to

defer

to the honor system. “I am not a person who wants to make more rules,†he

says. “I just want people to behave.â€

Originally published in Boston Magazine, November 2006.