Healthy Skepticism Library item: 4960

Warning: This library includes all items relevant to health product marketing that we are aware of regardless of quality. Often we do not agree with all or part of the contents.

Publication type: news

Angell M.
Your Dangerous Drugstore
NY Review of Books 2006 Jun 8
http://www.nybooks.com/articles/19055

Full text:

1.

On April 5, 2006, a New Jersey jury found that Merck’s arthritis drug
Vioxx
caused John McDarby, a seventy-seven-year-old retired insurance agent,
to
suffer the heart attack that left him debilitated in 2004. (The drug
was not
blamed for the heart attack of a second plaintiff in the same case.)
The
jury also found Merck guilty of consumer fraud for not warning doctors
and
the public of the drug’s cardiovascular risks. McDarby and his wife
were
awarded $4.5 million, plus another $9 million in punitive damages
because
the company was found to have misled the US Food and Drug
Administration
(FDA). Merck now faces about ten thousand similar lawsuits, and has
vowed to
fight every one of them. So far, there have been verdicts in four
cases‹two
for Merck and two against (the McDarby case and an earlier one in
Texas, in
which the plaintiff was awarded $253.5 million, which under Texas law
must
be cut to $26.1 million).¹ If there are more losses, and the chances
are
there will be, Merck, despite its defiant talk, may ultimately have to
try
to reach a settlement instead of fighting each case.²

The defeat was not just a loss for Merck, but for the industry as a
whole,
which has seen its reputation plummet in the past few years. Polls show
that
among American businesses, the pharmaceutical industry now ranks near
the
bottom in public approval‹above tobacco and oil companies, but well
below
airlines and banks and even insurance companies. This situation
contrasts
sharply with the generally high regard in which the industry was held
just a
few years ago.³

There are three main reasons for the drop in public esteem. First,
people
are growing increasingly skeptical about the industry’s justifications
for
its high and rapidly escalating prices. To many, it looks more like
simple
profiteering than what the industry claims it is‹a necessity to cover
high
research and development costs. People are beginning to realize that
even
after the pharmaceutical industry’s much-vaunted R&D expenditures, it
still
has enough left over to make it consistently one of the most profitable
industries in the US. Second, as more people began to purchase drugs
from
Canada in recent years, it became generally well known that prices in
the US
are much higher than in other countries. While the industry claims that
other countries are “free riders,” it seems to many Americans that it
is the
drug companies who are free riders. Finally, many older people have
become
all too aware of the fact that the new Medicare drug benefit, as a
result of
pressure from the powerful pharmaceutical lobby, specifically prohibits
Medicare from using its huge purchasing power to bargain with drug
companies
for lower prices (even though it is allowed to regulate doctors’ fees
and
hospital payments). This prohibition adds to the disillusionment with a
bill
that is not only weirdly byzantine but provides far less help than it
might,
and it increases resentment toward the pharmaceutical industry.
————————————————————————————————————

————————————————————————————————————

Much of what is wrong with the industry is explained in several recent
books. They include Merrill Goozner’s The $800 Million Pill, which
shows
that most innovative research on serious diseases like cancer and
HIV/AIDS
is done not by drug companies but in government and university labs.
Jerry
Avorn’s Powerful Medicines discusses the risks and benefits of the
drugs
themselves, and shows that many of them fall far short of their
marketing
pro-mises. John Abramson’s Overdosed America presents a clinician’s
view of
the misinformation that leads doctors to prescribe unnecessary and
possibly
harmful drugs. Jerome Kassirer’s On the Take explains how the medical
profession has allowed itself to be seduced by the billions of dollars
lavished on it by the drug companies (for example in subsidizing
medical
meetings of all types). Sharna Olfman’s No Child Left Different takes a
critical look at the promotion and overuse of psychoactive drugs in
children. Selling Sickness, by Ray Moynihan and Alan Cassels, explains
how
the pharmaceutical industry increases sales by convincing essentially
normal
people that they have chronic conditions (such as erectile dysfunction)
that
require lifelong drug treatment. Although each of these books
emphasizes
different parts of the system, they are remarkably consistent when they
overlap, and together they make a damning case, not just against the
industry but against our entire system for developing, testing, and
using
prescription drugs.⁴
————————————————————————————————————

The Vioxx story exemplifies many of the problems.⁵ It first came to
public
attention on September 30, 2004, when Merck announced it was pulling
Vioxx
from the market, citing a clinical trial that showed it doubled the
risk of
heart attacks and strokes.⁶ Vioxx had been heavily promoted to both
doctors and the public. The “direct-to-consumer” ads on television
featured
1976 Olympic gold medalist Dorothy Hamill skating effortlessly across
an
outdoor rink to the Rascals’ “It’s a Beautiful Morning“‹presumably free
of
arthritis pain, thanks to Vioxx. At the time the drug was withdrawn, an
estimated 20 million people had taken Vioxx, and it had yearly sales of
$2.5
billion. The withdrawal of Vioxx was front-page news and caused great
public
concern‹both among those who felt the drug was uniquely effective in
relieving their arthritis symptoms and among those who feared they
might
have a heart attack or stroke because of the drug. Merck’s stock price
fell
by more than a quarter on the day of the announcement, and market
analysts
began to speculate about the company’s uncertain financial future and
legal
liabilities.

Attention immediately turned to Pfizer’s Celebrex and Bextra.⁷ All
were in
the same class of drugs, called COX-2 inhibitors, and there were two
more in
late-stage development, Merck’s Arcoxia and Novartis’s Prexige.⁸ The
first
of them, Celebrex, which had preceded Vioxx on the market by a few
months,
was an even bigger success, with sales of $3.3 billion. The others were
what
are known as “me-too drugs“‹additional drugs in the same class. An
editorial
in The Wall Street Journal, loyal as always to the pharmaceutical
industry,
found something to celebrate. “The Vioxx withdrawal,” it said, “shows
why
choice in ‘me-too’ drugs is a good thing.”⁹ I wrote a letter to the
editor
pointing out that it was premature to conclude that Celebrex and Bextra
were
in the clear. “Since they are so much like Vioxx,” I said, “I would not
bet
my ice skates that they are not eventually shown to have similar
risks.”¹⁰

It didn’t take very long. Within months, there were reports that
Celebrex
and Bextra also increased the risk of heart attacks and strokes, at
least in
some patients at some doses.¹¹ But Pfizer announced that, unlike
Merck, it
would leave the drugs on the market, although it would stop advertising
them
to consumers, because, as its CEO explained to a television reporter,
whether and how to use the drugs were “complicated” matters that ought
to be
left to doctors in discussion with each patient. (He did not explain
why
that very sensible advice should not apply to other prescription drugs
promoted directly to the public.)

As confusion grew, the FDA appointed a special advisory panel to hold
hearings and advise it about how to handle the situation. There were
several
possible courses of action for the FDA. For example, all the COX-2
inhibitors could be pulled from the market immediately. Or Celebrex,
which
seemed safer than the others at usual doses (it acted like a weaker
version
of Vioxx), could be allowed to remain. (As is often the case with
me-too
drugs, apparent differences have a lot to do with the dose.) Or they
could
all be left on the market, including Vioxx, but with some new
guidelines
restricting their use.

The FDA advisory panel consisted mainly of members of two standing
advisory
committees‹one for arthritis and one for drug safety. During the
hearings
and deliberations, which were public, there were emotional testimonials
from
patients who claimed that one or another of the COX-2 inhibitors had
produced spectacular results after other types of painkillers had
failed.
The hearings lasted for three days in mid-February 2005, and the final
decision was prominently reported in the press.¹² Although the panel
agreed that COX-2 inhibitors as a class did indeed increase the risk of
heart attacks and strokes, it concluded that the benefits outweighed
the
risks (the vote was close in the case of Vioxx and Bextra). It
therefore
recommended that Celebrex and Bextra remain on the market and that
Vioxx be
allowed to return, perhaps with strong warnings on the labels for all
three,
and a moratorium on ads that appealed directly to consumers.

On April 7, 2005, however, following revelations that many panel
members had
financial ties to Merck or Pfizer, the FDA, which usually takes its
advisory
committees’ advice, decided differently. As expected, it announced that
Celebrex could remain on the market, with a strong warning on its
label. But
the agency asked Pfizer to take Bextra off the market, and indicated
that if
Merck wanted to bring Vioxx back, it would have a difficult battle.
————————————————————————————————————

The story of the approval and marketing of the COX-2 inhibitors
illustrates
nearly every major criticism of the pharmaceutical industry made in my
book
The Truth About the Drug Companies: How They Deceive Us and What to Do
About
It. Among other things I criticize the lax standards for approval of
drugs,
the conflicts of interest that pervade the system and influence
decisions,
the slowness of both industry and the FDA to respond to danger signals,
the
power of the industry’s huge marketing campaigns, and the baseless
justifications for me-too drugs.

In late 1998 and early 1999, Celebrex and then Vioxx were approved by
the
FDA. They were given rapid “priority” reviews‹which means the FDA
believed
them likely to be improvements over drugs already sold to treat
arthritis
pain. Was that warranted? Neither drug was ever shown to be any better
for
pain relief than over-the-counter remedies such as aspirin or ibuprofen
(Advil) or naproxen (Aleve). But theory predicted that COX-2 inhibitors
would be easier on the stomach, and that was the reason for the
enthusiasm.
As it turned out, though, only Vioxx was shown to reduce the rate of
serious
stomach problems, like bleeding ulcers, and then, mainly in people
already
prone to these problems, a small fraction of users. In other words, the
theory just didn’t work out as anticipated.

Furthermore, people vulnerable to stomach ulcers could probably get the
same
protection and pain relief by taking a proton-pump inhibitor (like
Prilosec)
along with an over-the-counter pain reliever.¹³ So the COX-2
inhibitors
did not really fill an unmet need, despite the one seemingly attractive
claim made in favor of them. Nevertheless, the FDA acted as if they
did, by
giving these drugs expedited review and approval.

In my book I discussed the conflicts of interest pervading the FDA,
including the fact that many members of FDA advisory committees are
paid
consultants for drug companies. Although they are supposed to recuse
themselves from decisions when they have a financial connection with
the
company that makes the drug in question, that rule is regularly waived.
With
that in mind, I checked the minutes of the 1999 advisory committee
meeting
that led to the approval of Vioxx. Sure enough, four of the six
members,
including the chairman, were granted waivers because they had a
“potential
for a conflict of interest.”¹⁴

Worse yet, of the thirty-two members of the 2005 panel that was charged
with
deciding whether the COX-2 inhibitors were safe enough to stay on the
market, ten had financial connections with one of the manufacturers,
according to a front-page story in The New York Times that appeared a
week
after the panel’s decision.¹⁵ As is often the case, these ten members
with
conflicts of interest were not disqualified. And as it turned out, they
voted 9­1 in favor of Vioxx and Bextra. Without their votes, the panel
would
have recommended that these two COX-2 inhibitors be removed from the
market
(there would still have been enough votes to keep Celebrex). This does
not
prove that these nine advisers were biased, but it certainly raises the
question, especially since Vioxx and Bextra were rejected by the
majority of
panel members with no known ties to the manufacturers. That is why FDA
advisory committees should not include people with conflicts of
interest, no
matter how expert they may be.
————————————————————————————————————

The clinical trial that caused Merck to withdraw Vioxx was designed to
see
whether the drug could prevent the recurrence of colorectal polyps; the
finding that the drug increased the risk of heart attacks and stroke
was an
accidental result of the trial. The company professed to be surprised.
Then
the CEO, Raymond Gilmartin, who claimed his wife took Vioxx right up
until
the drug was withdrawn, said the results were “unexpected.”¹⁶

But in fact, it could hardly have been a complete surprise. There had
been
signs of trouble for years.¹⁷ In 2000, a company-sponsored trial was
published in The New England Journal of Medicine comparing Vioxx with
over-the-counter naproxen in patients with rheumatoid arthritis.¹⁸
This
was called the Vioxx Gastrointestinal Outcomes Research, or VIGOR,
trial
(medical researchers and their sponsors love catchy acronyms), and it
was
intended to show that Vioxx was easier on the stomach than naproxen
(Aleve).
In relieving pain, the drugs proved to be the same, but those taking
Vioxx
had only half the risk of serious stomach problems. Unfortunately, the
study
also showed at least a fourfold increase in the risk of heart attacks.
The
details of the cardiovascular effects were not described in the
published
paper, but an FDA analysis indicated that the drug was more likely to
cause
heart attacks or strokes than to prevent stomach ulcers. Merck tried to
explain the alarming finding away by saying the difference probably
showed
that naproxen protects the heart, not that Vioxx harms it. But, of
course,
without testing that hypothesis, it was simply self-serving
speculation.
Moreover, within a year, other evidence came to light that Vioxx
increased
cardiovascular risks, and that Celebrex may do so as well.

In my book I discussed the power of the big pharmaceutical companies to
sell
just about anything. What Merck should have done after it got the
results of
the VIGOR trial was immediately launch a large enough clinical trial to
investigate the cardiovascular risks as quickly as possible. Instead, a
few
months later, it signed Dorothy Hamill to skate its problems away. The
company reportedly spent $160 million on direct-to-consumer ads for
Vioxx in
2000, and continued to spend approximately $100 million a year during
the
next four years.¹⁹ The costs of even a very large clinical trial
would
almost certainly have been less than what the company spent on ads. But
as
expensive as they are, the costs of direct-to-consumer ads are small
compared with what drug companies spend promoting their products to
doctors.
In a variety of expensive ways doctors became convinced‹just as the
public
did more cheaply‹that Vioxx was some sort of a breakthrough. The fact
that
it was no more effective than naproxen, or presumably other
over-the-counter
remedies, was a fact soon forgotten.

That the advisory panel recommended halting direct-to-consumer ads
highlighted the hollowness of the pharmaceutical industry’s contention
that
such ads are “educational“‹designed to encourage patients to discuss
medical
problems with their doctors. It should be obvious that there is nothing
educational about watching Dorothy Hamill pitch a drug or about the
other
prescription drug ads we see on television. They are meant to persuade
patients (and doctors) to use the drug. And they work‹as they did
spectacularly well in the case of the COX-2 inhibitors. That is why
every
other advanced country except New Zealand does not permit such ads. But
despite the fact that senior officials of the FDA, including the last
two
commissioners, have repeatedly endorsed the fiction that
direct-to-consumer
ads are educational, the advisory panel clearly knew better. If ads
were
truly educational, panel members would not have recommended a
moratorium on
broadcasting them. [20]

In a sense, Merck was doing what big drug companies often do. It was
touting
the benefits of its drug (such as they were), downplaying or explaining
away
the risks, and marketing it as though it were a medical miracle. Less
explicable is the dereliction of the FDA. If Merck didn’t want to
launch a
study of the cardiovascular effects of Vioxx (and it had nothing to
gain
commercially by doing so), why didn’t the FDA insist on it? After all,
the
FDA’s responsibility is to ensure that prescription drugs are safe and
effective, and there was clearly something that needed looking into
here.
The FDA should also have taken a close look at the ads, since one of
its
jobs is to ensure that they are accurate and balanced‹which they
obviously
were not.

But the FDA did nothing. Later, it protested that it doesn’t have the
authority to mandate additional studies once a drug is marketed, but
that is
sophistry. The FDA has the authority to pull drugs off the market, and
that
threat would have been enough to get Merck to organize a trial.
Finally, in
2002, after a year of wrangling, it got Merck to add a tepid warning to
the
drug’s labeling information‹the material in small print that comes with
prescription drugs (and that few actually read). That hardly met the
agency’s responsibility. The part of the FDA that approves new drugs
now
receives half of its funding from “user fees” paid by drug companies
for
each drug evaluated. These were first authorized by Congress in 1992,
and in
return the FDA was required to speed up its review of drugs. I warned
in my
book about the baleful effects of the user fees, which put the FDA on
the
payroll of the industry it regulates. This story brings that warning
home.

2.

The Vioxx case underlines the importance of clinical trials in deciding
whether drugs work or not. Without them, doctors and patients would
have to
decide on the basis of personal accounts indicating whether or not a
given
patient seems to improve. That is an unreliable (not to mention
dangerous)
method. As I wrote:

The assumption that a drug works if a patient gets better does not
allow for
natural variations in the illness, for the placebo effect (the tendency
of
both doctors and patients to imagine a drug is working), for all the
other
times when the drug might fail, or for the possibility that another
drug
might have worked better.

That is why clinical trials were such an important medical advance when
they
were first introduced in the middle of the twentieth century, and why
the
FDA requires clinical trials rather than a collection of testimonials
to
decide whether drugs are safe and effective.

I mention this because the public hearings held by the FDA advisory
panel
permitted testimonials from people who said they wanted the COX-2
inhibitors
left on the market because nothing else relieved their pain. The panel
was
reportedly much influenced by these testimonials (could that have
explained
the pro-Celebrex vote by panel members not on Pfizer’s payroll?), and
it
ultimately concluded that, although the drugs should be used far less
widely
than they were, they might be uniquely effective for some people. But
while
that is possible, there was no evidence on which to base that
conjecture.

Not only are testimonials an unreliable way to judge a drug’s
effectiveness,
they are particularly useless when those giving the testimony are
selectively chosen. According to the transcript, at least one of the
patients who spoke at the hearings was brought there by Pfizer, the
maker of
Celebrex and Bextra. I have not seen any evidence that patients who had
suffered heart attacks or strokes while on these drugs were brought to
Washington to testify; nor, so far as I know, were those who had tried
a
COX-2 inhibitor but preferred Advil or Aleve.

The notion that testimonials are useful in evaluating drugs reflects
the
biases of some doctors (mainly those in clinical practice) and much of
the
public. Many patients like to think they are uniquely different from
others,
not only as persons, but biologically. However, biological variations
among
patients are probably far less significant than is widely believed, and
would need verification, in any case. Clinicians, for their part, want
as
many choices of drugs as possible, even if they have little basis for
choosing among them. When a drug doesn’t seem to work, they want to be
able
to say, “Here, try this and see if that’s better.” So it should not be
surprising that testimonials played such a big part in these hearings.
They
were open hearings, and it would have taken a brave panel member to
point
out publicly that testimonials are not a good basis for making a
decision
about the benefits of drugs.

Drug companies are quick to exploit the view that there is great
biological
variability among patients; it is one of their justifications for
turning
out so many me-too drugs. They like to present me-too drugs as backups
for
one another. But there is little evidence to support the notion that if
a
particular drug doesn’t work for a patient, another one in the same
class
will. Drug companies don’t test their me-too drugs on patients who have
found a similar drug ineffective, so there is no way to know for sure.
But
much of what may look like differences among me-too drugs probably has
mainly to do with the size of doses. It may be, for example, that a
double
dose of Celebrex would act just like Vioxx for virtually everyone.

Even if we grant the possibility that some people may respond very
differently to these drugs, does that justify accepting a greatly
increased
risk of heart attacks and strokes? Since those who most need pain
relievers
for arthritis are precisely older people who are most vulnerable to
cardiovascular disease, the drugs have been estimated to have caused
tens of
thousands of heart attacks among the millions of people who have taken
them
regularly.²¹ That is a tremendous cost to balance against the dubious
proposition that the drugs offer something unique for pain relief. It
is the
FDA’s job to see that the benefits of prescription drugs outweigh the
risks.
It seems clear to me that the agency failed to do so in this case.
————————————————————————————————————

The courtroom is not a good place to resolve questions like whether
Vioxx
caused someone’s heart attack. For one thing, when there are other
possible
causes of a medical condition, it’s usually impossible to know which
one was
responsible in any specific case. The best we can do is deal with
statistical probabilities. For example, if we look at large numbers of
people and find that heart attacks are more than twice as common in
those
who took Vioxx (as some studies have found²² ), then we can say that
the
drug outweighs all other risks in the average person like those in the
trials. But our legal system requires juries to determine causation in
particular individuals, with particular sets of risks, something that
is
rarely possible. It is an illusion of our tort system to think that we
can,
and it is one reason these kinds of cases yield such inconsistent
verdicts.
The best we can do is assume each person is typical of those studied in
clinical trials.

John McDarby had a number of other conditions that could have affected
his
heart, such as diabetes and clogged arteries, and Merck made the case
that
his heart attack should be attributed to them, not Vioxx. This
strat-egy had
been successful in earlier cases. But McDarby’s lawyers stood the
argument
on its head. They made the case that precisely because of these other
heart
risks, he was especially vulnerable to the dangerous effects of
Vioxx‹in
their words, “the last person who should have been on Vioxx.” That is
certainly a commonsensical view, and clearly the jury saw it that way.
Essentially, they were persuaded that a push is more dangerous if
you’re
standing on the edge of a cliff.

The punitive damages in the McDarby case were based largely on the
jury’s
finding that Merck had misled the FDA by not supplying it with an
internal
analysis the company had done of Vioxx’s risks. Merck argued that it
withheld the analysis because it was flawed, but had supplied all the
underlying data. Whatever the truth about McDarby’s claims, the FDA
certainly had enough information to take stronger action years ago.

We have an FDA precisely because we know that drug companies, given
their
inherent conflict of interest, should not be left to decide on their
own
whether their products are safe. Caveat emptor may be a reasonable
approach
for many consumer products, but not for prescription drugs. But the
Vioxx
story underscores the extent to which the FDA has come to see itself as
representing the drug companies, not the public.
————————————————————————————————————

Two reforms are necessary. First, the conflicts of interest that
pervade the
agency should be eliminated. The Prescription Drug User Fee Act (PDUFA)
that
authorized drug companies to pay user fees in return for quick approval
of
their drugs comes up for renewal in 2007. Congress should let it die,
and
instead appropriate adequate support from public funds for this vitally
important agency. The FDA should also prohibit experts who consult for
drug
companies from sitting on its advisory panels. No one’s expertise is
indispensable, contrary to the current practice of granting virtually
automatic waivers on those grounds.

Second, the FDA should be made much more transparent. Drug companies
are
required to inform the agency about all the clinical trials they
sponsor on
drugs for which they are seeking FDA approval. But the agency does not
make
the studies public without permission of the sponsor, and drug
companies
naturally publish only the most favorable results. By allowing less
favorable results to remain buried, the agency puts proprietary
interests
ahead of the public interest, and doctors and the public come to
believe
prescription drugs are better than they are. That should stop. All
studies
involving human subjects should be registered at inception in a
publicly
available, central database, and the salient results added at
completion.

These reforms will require congressional legislation‹an uphill battle,
in
view of the power of the pharmaceutical lobby in Washington. That power
will
need to be offset by concentrated pressure from citizen and advocacy
groups
with an interest in regulating prescription drugs, something that has
so far
been lacking. But the spotlight does belong squarely on the FDA. That,
after
all, is where the public’s protection should lie, not with juries after
the
damage is done.

Notes

[1] For full accounts see Alex Berenson, “A 2nd Loss for Merck Over
Vioxx,”
The New York Times, April 6, 2006, and “Vioxx Jury Adds More in
Damages,”
The New York Times, April 12, 2006.

[2] Merck recently lost another case, when a jury in Rio Grande, Texas,
awarded $32 million (which must be reduced to $8 million) to the family
of a
man who died of a heart attack after taking Vioxx.

[3] See Kaiser Family Foundation news release, “Americans Value the
Health
Benefits of Prescription Drugs, But Say Drug Makers Put Profits First,
New
Survey Shows,” February 25, 2005, www.kff.org/kaiserpolls/pomr022505nr
.cfm.

[4] Merrill Goozer, The $800 Million Pill: The Truth Behind the Cost of
New
Drugs (University of California Press, 2004); Jerry Avorn, Powerful
Medicines: The Benefits, Risks, and Costs of Prescription Drugs(Knopf,
2004); John Abramson, Overdosed America: The Broken Promise of American
Medicine (HarperCollins, 2004); Jerome P. Kassirer, On the Take: How
Medicine’s Complicity with Big Business Can Endanger Your Health(Oxford
University Press, 2004); No Child Left Different, edited by Sharna
Olfman
(Praeger, 2006); Ray Moynihan and Alan Cassels, Selling Sickness: How
the
World’s Bigest Pharmaceutical Companies Are Turning Us All into
Patients
(Nation Books, 2005).

[5] I tell the story in the epilogue of the paperback edition of my
book,
The Truth About the Drug Companies: How They Deceive Us and What to Do
About
It(Random House, 2005).

[6] For full accounts of the withdrawal, see Gina Kolata, “A Widely
Used
Arthritis Drug Is Withdrawn,” The New York Times, October 1, 2004, and
Alice
Dembner, “Maker Takes Vioxx off Market,” The Boston Globe, October 1,
2004.

[7] Andrew Pollack, “New Scrutiny of Drugs in Vioxx’s Family,” The New
York
Times, October 4, 2004.

[8] One of the causes of pain and inflammation are chemicals in the
body
called prostaglandins. Many over-the-counter arthritis drugs act by
inhibiting two enzymes, called cyclooxygenases, responsible for the
effects
of prostaglandins. But the first of these enzymes also protects the
lining
of the stomach. COX-2 inhibitors were designed to inhibit only the
second,
thus protecting the stomach while reducing pain.

[9] “A Vioxx Elegy,” The Wall Street Journal, October 1, 2004.

[10] Marcia Angell, “Merck Downplayed Risks of Its Vioxx,” The Wall
Street
Journal, October 7, 2004.

[11] As usual, some of the best reporting about the pharmaceutical
industry
came from the New York Times reporter Gardiner Harris. See his stories
“Drug
Trial Finds Big Health Risks in 2nd Painkiller,” The New York Times,
December 18, 2004, and “New Study Links Pfizer’s Bextra, Similar to
Vioxx,
to Heart Attacks,” The New York Times, November 10, 2004.

[12] Gardiner Harris, “FDA Is Advised to Let Pain Pills Stay on
Market,” The
New York Times, February 19, 2005.

[13] Proton-pump inhibitors are drugs that inhibit the normal secretion
of
hydrogen ions (protons) by the stomach. That interferes with the
formation
of stomach acid, which in turn reduces the risk of heartburn and
ulcers.

[14] For a transcript of that meeting, see
www.fda.gov/ohrms/dockets/ac/cder9t.htm#Arthritis.

[15] Gardiner Harris and Alex Berenson, “10 Voters on Panel Backing
Pain
Pills Had Industry Ties,” The New York Times, February 25, 2005.

[16] Quoted in Anna Wilde Mathews and Barbara Martinez, “E-Mails
Suggest
Merck Knew Vioxx’s Dangers at Early Stage,” The Wall Street Journal,
November 1, 2004.

[17] For several accounts of the longstanding safety concerns about
Vioxx,
see Mathews and Martinez, “E-Mails Suggest Merck Knew Vioxx’s Dangers
at
Early Stage”; Eric J. Topol, “Failing the Public Health‹Rofecoxib,
Merck,
and the FDA,” The New England Journal of Medicine, October 21, 2004;
Barbara
Martinez, “Vioxx Lawsuits May Focus on FDA Warning in 2001,” The Wall
Street
Journal, October 5, 2004.

[18] Claire Bombardier et al., “Comparison of Upper Gastrointestinal
Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid
Arthritis,”
The New England Journal of Medicine, November 23, 2000.

[19] The $100 million figure was widely reported; see, for example,
Topol,
“Failing the Public Health”; see also www
.todaysseniorsnetwork.com/excessive _ads.htm.

[20] In April of this year, Pfizer resumed advertising Celebrex after a
steep drop in sales during the moratorium. The ad included the
following
text: “Important information: Celebrex may increase the chance of a
heart
attack or stroke that can lead to death.”

[21] For estimates, see Eric J. Topol, “Failing the Public Health.
Also,
testimony of David J. Graham, associate director for science and
medicine in
the FDA’s Office of Drug Safety, before the Senate Finance Committee,
November 18, 2004.

[22] For an overview of studies, see Peter Jüni et al, “Risk of
Cardiovascular Events and Rofecoxib: Cumulative Meta-analysis,” The
Lancet,
December 4, 2004.