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Four Corners -

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Read the transcript of Jonathan Holmes' report into the Vioxx controversy.

Date: 11/04/2005

NEWSREADER: Hundreds of thousands of Australians are being warned to stop taking a popular
arthritis medication because it increases their risk of heart attack. The drug, Vioxx, has been
withdrawn from sale around the world.

JONATHAN HOLMES: Even though 300,000 Australians were taking VIOXX, its recall last October caused
barely a ripple in Australia. But it's caused consternation in America, where VIOXX has contributed
to huge numbers of heart attacks and strokes.

MAN: This range of 88,000 to 139,000 would be the rough equivalent of 500 to 900 aircraft dropping
from the sky.

JONATHAN HOLMES: The medical malpractice lawyers are aiming to take billions of dollars from
VIOXX's maker, Merck & Co.

PAUL SIZEMORE: Right now we have open 22,000 cases.

JONATHAN HOLMES: And attention has focused on the regulator, which failed to protect the public.

ERIC TOPOL: This is the worst prescription withdrawal in medical history. The largest number of
people who were affected with unintended harm. We need to learn from this. We can't have something
like this happen again.

JONATHAN HOLMES: Tonight on Four Corners, the story of a best selling medicine that killed and the
warning signs that came long before its total recall.

Hervey Bay, on Queensland's Sunshine Coast, is one of those places Australians hope to retire to
one day. But too often the dreams of an active and healthy life after work are spoiled by the
crippling pain of arthritis.

WOMAN: First gear.

JONATHAN HOLMES: Water aerobics is the only form of exercise some arthritis sufferers can tolerate.
Trish Hunsley is younger than most in the pool. She was only 40 when she first suffered the painful
symptoms of osteoarthritis in her back. For her, back in 2001, VIOXX came as a godsend.

TRISH HUNSLEY: I tried Imbrufen and it just made me sick. Pains in the stomach. Our doctor said,
"There's another drug on the market which is friendly to the stomach", which was VIOXX. It worked
perfectly. I had no problems.

JONATHAN HOLMES: No problems with your stomach?




JONATHAN HOLMES: So that was great?


JONATHAN HOLMES: Trish Hunsley took VIOXX every day for more than three years. Apart from her
arthritis, she was a fit and healthy 44-year-old, a non-smoker, with no history in her family of
heart disease. Then, in September 2003, she suffered a near-fatal heart attack.

TRISH HUNSLEY: Chest pain just in the middle of my chest, and it was just excruciating. It just -
yes, I couldn't handle it. I was stressing about it and my husband came in and saw my face and he
said I was as white as a ghost and called the ambulance.

JONATHAN HOLMES: When she got to the Wesley Hospital in Brisbane they told Trish Hunsley that she
had a 100-per-cent blockage in her coronary artery. She had a stent and a defibrillator implanted
and was in hospital for 14 days.

TRISH HUNSLEY: My life's just been stolen from me, as far as I'm concerned. I was healthy before
that, except for the arthritis. I just feel I don't have a life anymore, that I'm just ruled by
this heart problem now.

JONATHAN HOLMES: Her cardiologist told Trish Hunsley at the time that he couldn't explain her heart
attack. It wasn't until VIOXX was withdrawn from the market last October that she had any idea that
it might've been to blame.

TRISH HUNSLEY: And I'm taking more drugs now than I ever did and I just get so tired.

JONATHAN HOLMES: Now she's suing Merck's Australian subsidiary, Merck Sharp & Dohme.

TRISH HUNSLEY: They've stolen people's lives or people have died from it, so I feel very strongly
that they have done wrong by the public.

JONATHAN HOLMES: The higher the daily dose, the more dangerous VIOXX was. Fortunately, the high
doses common in America were never authorised here. But the drug may still have killed four times
as many Australians as the Bali bomb.

PROF LES CLELAND: By our calculations, there would have been certainly more than a thousand events.

JONATHAN HOLMES: Out of those events how many would you expect potentially to be fatal?

PROF LES CLELAND: Oh, perhaps 30 per cent.

JONATHAN HOLMES: In the United States, the toll was certainly far higher.

ERIC TOPOL: When you add up all the events that occurred, it would make 9/11 look like nothing.
It's well over 100,000 heart attacks. All of us agree on that. Somewhere between 100, 000, possibly
up to 160, 000. David Graham has forecasted that about 40,000 deaths may have occurred.

JONATHAN HOLMES: Survivors and relatives are now suing. The Alabama law firm that's leading the
charge against Merck & Co has 22, 000 cases on its books.

PAUL SIZEMORE: Merck knew that there was a problem with VIOXX in the mid-1990s. It's not just
attorneys in the US or in Australia or in Europe saying this, we actually have internal memoranda,
documents, that showed definitively that there was a problem. This occurred back in 1998...

DAVID GRAHAM: ...underestimate the actual population impact.

JONATHAN HOLMES: Merck strenuously denies those claims. The court battles will, no doubt, go on for
years. In the meantime, experts around the world are urgently reviewing the safety of the whole
family of drugs to which VIOXX belongs, including the most successful of all - Celebrex. . .

DAVID GRAHAM: Looking at COX-2 usage and acute myocardial infarction.

PROF ALASTAIR WOOD: The risk is real. How do I know it's real? Because we've got now a number of
studies for all three of the drugs that show that it increases the risk of heart attacks and

WOMAN: Up ... and drop. Up ... and drop. And reach. Reach for the roof. Royal wave.

JONATHAN HOLMES: Yet just five years ago, these drugs were being hailed as the new miracle
breakthrough for tens of millions of arthritis sufferers.

WOMAN: Stop you grinding those little joints in your neck.

JONATHAN HOLMES: Many, though by no means all, are middle-aged and elderly.

WOMAN: And relax.

JONATHAN HOLMES: Inflamed and painful hips and knees and fingers can make their lives a misery.

WOMAN: And down.

JONATHAN HOLMES: Since the 1970s, a whole family of so-called non-steroidal anti-inflammatory
drugs, with brand names like Aleve and Naprosyn, Advil and Voltaren, had successfully treated the
pain and inflammation.

WOMAN: One minute. I'll just watch her take her medication.

JONATHAN HOLMES: But as rheumatologists and GPs were all too well aware, the so-called NSAIDs had
one major drawback.

DR DAVID BORENSTEIN: The problem with these medicines is that they caused gastrointestinal
difficulties. They would cause nausea, vomiting, or they would cause bleeding in the stomach from

JONATHAN HOLMES: The problem has been understood by scientists for decades. Arthritis is caused in
damaged joints when the immune system produces too much of a protein called prostaglandin, which
causes pain and inflammation. It's triggered by an enzyme - cyclo-oxygenase, or COX for short.
Traditional anti-inflammatory drugs block the action of the COX enzyme. That means less
prostaglandin, and so less pain and swelling. But there is a price elsewhere in the body, because
prostaglandin also produces a mucus lining on the stomach wall, which protects it from our
digestive acids. By blocking the COX enzyme, the older anti-inflammatory drugs can have an unwanted
side effect; an increased rate of stomach ulcers and gastric bleeding.

DR DAVID BORENSTEIN: And if it's in the wrong person at the wrong time, they can have a big enough
bleed into the stomach that they exsanguinate. They actually lose all of their blood into their
stomach. They become hypotensive, their blood pressure gets too low and their heart will stop.

PROF RIC DAY: We estimated in Australia about 200 to 400 people, or even up to 600 people, are
dying each year from drug-induced gastrointestinal bleeding. So there was a major public-health
issue, and in fact this was considered to be the biggest and most important adverse drug reaction
around the world.

JONATHAN HOLMES: Then, in the 1980s, scientists made a crucial discovery. There were in fact not
one COX enzyme, but two so-called isoenzymes - COX-1 and COX-2. COX-1 triggered the prostaglandins
in the stomach wall, COX-2 triggered them around damaged joints, causing pain and swelling. If
COX-2 could be selectively blocked, the pain and swelling could be reduced, while COX-1 would
continue to protect the lining of the stomach.

In pharmaceutical company labs around the world, the race was on to develop a so-called COX-2

WOMAN: With Celebrex I will no longer give in to the joint pain of osteoarthritis.

WOMAN: With Celebrex, I will not stop at nine ...

JONATHAN HOLMES: The winner of the race was Celebrex - manufactured by Pharmacia and marketed by
Pfizer. It was approved in the United States in late 1998 and was launched with a massive
advertising campaign.

MAN: Ask your doctor about Celebrex.

WOMAN: With all the great memories has come another thing I thought I'd never experience; the pain
of osteoarthritis.

MAN: VIOXX is here - the prescription medicine for osteoarthritis pain.

JONATHAN HOLMES: A few months later Merck & Co joined the race with VIOXX.

MAN: Ask your doctor if VIOXX is right for you. VIOXX - for everyday victories.

SNGING: Celebrex

MAN: One little pill.

WOMAN: Discover Celebrex.

JONATHAN HOLMES: Hundreds of millions of dollars were spent in a battle for consumers' hearts and

MAN: Celebrex relieves arthritis pain, plus inflammation and stiffness, too.

JONATHAN HOLMES: Despite the hype, neither drug can claim to be a more effective painkiller than
older, cheaper drugs. They'd been taken daily by millions for years. Yet the Food and Drug
Administration, the FDA, had given them market approval in a mere six months.

DAVID GRAHAM: They had what are called accelerated approvals, so the reviews were done quickly, the
approvals happened quickly. On the basis of this theory that it was believed that they would prove
safer to the intestinal tract, without actually having the evidence in hand.

JONATHAN HOLMES: They had some short-term endoscopic studies?

DAVID GRAHAM: They had short-term studies. But no-one would accept those as evidence of a clinical

WOMAN: Hi, Tim.

MAN: Hi. Hi, how ya doin'?

JONATHAN HOLMES: That didn't stop doctors in America writing millions of prescriptions on the
strength of a hope that the theory of COX-2 inhibition would work.

PAUL SIZEMORE: It's a very sexy, alluring type of theory, Jonathan, and everyone inside the
scientific community wanted that theory.

NEWSREADER: But now science has come up with a drug that can ease the pain of arthritis without the
harmful side effects that accompany so many other painkillers. More on that from Scott Bevan.

JONATHAN HOLMES: The media latched on, too, presenting unproven theory as fact, even before
Celebrex or VIOXX had been approved for sale in Australia.

REPORTER: But now there's a breakthrough. A new drug, dubbed a super-aspirin, has been developed.

JONATHAN HOLMES: Australia's Therapeutic Goods Administration, the TGA, gave Celebrex fast-track
approval in mid-1999. A year later the Government agreed to list it for subsidy through the
Pharmaceutical Benefits Scheme.

POLITICIAN: Good news; we're funding a drug category called COX-2 inhibitors. The drug is Celebrex.

JONATHAN HOLMES: Helped by community announcements indirectly funded by Pfizer, sales of Celebrex
took off in Australia. In early 2001 VIOXX would join it on the PBS.

MAN: If arthritis is stopping you from doing the things you enjoy, ask your doctor about the
exciting new arthritis treatments.

MUKESH HAIKERWAL: It was sold very well as being a medication that would cure all ills without any
side effects. There was an awful lot of from-the-public pressure because of direct-to-public
advertising, albeit surreptitiously, to come and prescribe this tablet.

JONATHAN HOLMES: You had patients asking for it?


JONATHAN HOLMES: There's no doubt that many patients found the COX-2 inhibitors easier to tolerate
than the older drugs.

DR DAVID BORENSTEIN: The medicine works well for their musculoskeletal complaints but hasn't
bothered their stomach at all.

JONATHAN HOLMES: And you found that quite common?


JONATHAN HOLMES: Short-term tests using endoscopes had shown that over a few weeks, both Celebrex
and VIOXX caused many fewer ulcers than older anti-inflammatory drugs.

But a medicine that reduces mild ulcers and unpleasant stomach pains isn't necessarily saving
lives. Before they could claim their drugs caused fewer serious side effects, the makers of
Celebrex and VIOXX had to prove it. So Pharmacia and Merck funded clinical trials centres all over
the world, including Australia, to recruit thousands of patients for two major long-term trials.
The Celebrex trial was known as CLASS, the VIOXX trial, VIGOR.

Controversially, only the six-month results of the CLASS study were published. They showed a
significant reduction in gastrointestinal side effects. But over 12 months, the study showed,
Celebrex's results were no better than some of the drugs it was being compared to.

PROF LES CLELAND: I was not convinced there was any advantage over Diclofenac, for example, and
that was a comparator in the CLASS study.

JONATHAN HOLMES: Professor Les Cleland is one of Australia's leading rheumatologists and a
pharmaceutical sceptic. In his view Celebrex is no more COX-2 selective and no less dangerous to
the stomach than cheaper and older drugs like Voltaren. VIOXX, he says, is a different matter.

PROF LES CLELAND: It's a much more selective COX-2 inhibitor, almost 10 times more selective than

JONATHAN HOLMES: And indeed the VIGOR trial for VIOXX had more dramatic results than Celebrex for
good and ill. Half of about 8,000 rheumatoid arthritis patients were randomly assigned to 50mg of
VIOXX a day. In most trials the other half would have been given a placebo, or sugar pill, but that
wasn't possible when the subjects were suffering from rheumatoid arthritis.

PROF DAVID HENRY: Patients who are having chronic pain and stiffness due to inflammation in their
joints will not tolerate going on a completely inactive medication. They'll be in pain, they won't
sleep properly, they're going to feel miserable. They're quickly going to drop out of the trial or
start to take medication of their own, which will hopelessly bias the results of the study.

JONATHAN HOLMES: In other words you've got to compare the new medicine with an older one?

PROF DAVID HENRY: With the old one, yes.

WOMAN: Are you feeling okay? Excellent. That's terrific.

JONATHAN HOLMES: The older medicine chosen for the VIGOR trial was an NSAID called Naproxen and
that would turn out to be crucial. The 12-month VIGOR trial showed that even at high doses, VIOXX
caused less than half as many serious ulcers and gastric bleeds as Naproxen. That was the good
news. The bad news; the patients on high-dose VIOXX suffered four or five times more myocardial
infarcts, or in simpler and more frightening terms, heart attacks.

Professor Ric Day of St Vincent's Hospital in Sydney was one of the principal investigators on the
VIGOR trial.

PROF RIC DAY: When the results came out we were very surprised. We didn't expect to see this
difference in myocardial infarcts that was actually seen.

JONATHAN HOLMES: It was potentially devastating news for Merck. Already VIOXX was promising to earn
them billions, but if it were really increasing the risk of heart attack four-fold, it could be
endangering tens of thousands of people worldwide.

PROF ALASTAIR WOOD: Millions of people were taking these drugs. Estimates range up to 50 million
people. Secondly, many of the people who are taking these drugs are people with arthritis, people
with osteoarthritis particularly, who are relatively elderly, who are in the risk demographic for
having heart attacks. Thirdly, they tend to take these drugs for prolonged periods of time. These
all intersect to produce the potential for a major public health problem.

JONATHAN HOLMES: But when the VIGOR results were published in the prestigious New England Journal
of Medicine in November 2000, Ric Day and his fellow authors had a soothing explanation. Probably,
they said, it wasn't VIOXX that was causing heart attacks, the comparator drug Naproxen was acting
like aspirin to prevent them.

PROF RIC DAY: I think it was put forward as a hypothesis but it was put forward strongly as a
hypothesis and I think it was a pretty good one. Naproxen's an aspirin-like drug. What we do know
is Naproxen is a very good inhibitor of platelets, exactly what aspirin does, and why we think it
works to prevent heart attacks. I thought it was a good explanation.

MAN: Mr Gilmartin - Raymond.

JONATHAN HOLMES: So, naturally, did Merck. They've declined to speak to Four Corners, but their
global CEO testified to a US Senate Committee last year.

MAN: We look forward to your testimony and thank you for your patience.

JONATHAN HOLMES: The Naproxen theory held water, he argued, because tests comparing VIOXX to other
drugs had not revealed a problem.

RAYMOND GILMARTIN: In these studies, there was no difference in the rate of cardiovascular events
between VIOXX and placebo or between VIOXX and non-Naproxen NSAIDS.

GURKIPAL SINGH: I was shocked. I was completely shocked. The news came from out of the blue. And
Merck offered an explanation, "Oh, VIOXX doesn't increase the risk, it's Naproxen that decreases
the risk. Therefore there is no problem, life goes on."

JONATHAN HOLMES: Many independent experts were sceptical of the Naproxen theory, to say the least.
Dr Gurkirpal Singh is a leading researcher in the field. Originally a fan of COX-2 inhibitors, he's
now become a critic of Merck and the FDA, much in demand in Washington by congressional committees
investigating the VIOXX affair.

GURKIPAL SINGH: I just couldn't believe that Naproxen could account for the 500 per cent difference
in heart attacks between VIOXX and Naproxen.

JONATHAN HOLMES: Even aspirin, argued the sceptics, reduces heart attacks by only 30 per cent. It
can't explain a difference of 400 or 500 per cent.

GURKIPAL SINGH: So you're offering an alternative explanation without exploring the other
alternative, which means that VIOXX could also increase the heart attack risk. That is also a

JONATHAN HOLMES: Indeed, say the doubters, there's a plausible mechanism to explain why highly
selective COX-2 inhibitors like VIOXX might raise the risk of heart attacks.

The COX enzymes, it turns out, are busy in our blood vessels producing two chemicals which normally
balance each other. Thromboxane, produced mainly by COX-1, encourages veins and arteries to narrow
and platelets in the blood to clump together. Prostacyclin, produced mainly by COX-2, keeps veins
and arteries open and discourages clotting.

DR ERIC TOPOL: So if you block prostacyclin, you're now messing with Mother Nature in terms of
promoting clotting in some people.

PROF LES CLELAND: There's a basis for believing it makes it makes it more likely that someone might
form a clot.

JONATHAN HOLMES: And clots cause heart attacks and strokes?

PROF LES CLELAND: Strokes and so on, yes.

JONATHAN HOLMES: But for the next four years Merck's scientists and salesmen were hard at work,
from the huge medical conferences, where tens of thousands of doctors convene, to one-on-one chats
in individual surgeries. The message; the VIGOR trial showed major gastrointestinal benefit. The
cardiovascular results could be explained entirely by the aspirin-like effect of Naproxen. And
that's what most doctors came to believe.

DR ERIC TOPOL: If you were to walk around these same meetings in 2001 and 2002. . .2003, you would
see COX-2 symposiums everywhere and they would be having consultants that work for the company
giving lectures about how there's no problem with the heart, "These medicines are good for patients
with heart disease." It was extraordinary to see this. And when you get up in the morning, under
the door would be the advertisements for the symposia and you say, "How could this possibly - this
hoodwinking of the medical community is atrocious."

JONATHAN HOLMES: It's a measure of Dr Eric Topol's stature as a cardiologist that he was the
keynote speaker at this year's conference of the American College of Cardiologists in Orlando,
Florida. But when he authored a paper in 2001in a prominent journal arguing that VIOXX, and indeed
all COX-2 inhibitors, may well be causing heart attacks, Dr Topol found himself under ferocious

DR ERIC TOPOL: They had all their consultants, as well as employees, make statements about how our
paper was erroneous, it was flawed, our analysis was tortured. I mean, they made statements that
were just exceptional - no, degrading, debasing. And they just kept doing that for years.

JONATHAN HOLMES: Merck's CEO has told the US Senate that his company behaved impeccably throughout.

RAYMOND GILMARTIN: We have promptly disclosed the results of numerous Merck-sponsored studies to
the FDA, physicians, the scientific community and the public and participated in a balanced
scientific discussion of its risks and benefits.

JONATHAN HOLMES: But the US regulator, the FDA, didn't think so. In September 2001 it issued a
blistering public letter to Mr Gilmartin, warning him that Merck's claims for VIOXX's safety were
out of order.

But that example of plain speaking was entirely untypical of the way the FDA has dealt with the
issue for most of the past five years. The agency did almost nothing itself to warn doctors of the
possible dangers of VIOXX. From the time it got the VIGOR test results, it took more than two years
to persuade Merck to make a modest change to the VIOXX label, the detailed prescribing information
that accompanied the drug. Buried deep in the text, it was hardly a red alert to doctors.

PROF ALASTAIR WOOD: I have no understanding, as a physician, what that means. Does that mean the
patient should swallow it slowly? Should they take it with the lights on? What does it mean? What
do I do with that? I'm not being facetious. What do I do, as a physician, with that information?
You can't be cautious in your interaction, you either don't do it or you do do it. It's like
jumping out of a plane cautiously.

JONATHAN HOLMES: The experience of Jim Albright gives some indication of how ineffective the label
change was. He was a fit and active 40-year-old who drove trucks for a living through rural
Pennsylvania when he contracted rheumatoid arthritis in 1998. He was prescribed VIOXX and it
worked. He kept on trucking until July 27 2002, three months after the VIOXX label was changed.
That was the day he suffered a severe heart attack. Fortunately, it happened at home and not on the
road, or Jim Albright wouldn't be here to tell the tale.

JIM ALBRIGHT: I liken it to a small elephant just sat down on my chest. I was profusely sweating, I
couldn't breathe, my blood pressure dropped way low. They had to stop on the way to the hospital to
let one of the head technicians catch up and actually get in the ambulance to stabilise me, to get
me to the hospital.

JONATHAN HOLMES: After the heart attack, as far as you're aware, your doctor didn't have any doubts
about keeping you on VIOXX?


JONATHAN HOLMES: Never discussed the fact that it might have contributed?


DAVID GRAHAM: Heart attack is the leading killer of Americans. You know, we have, you know -
there's 900, 000 cases of heart attack a year and 400,000 people a year die from heart attacks. We
have a drug now that's going to increase your risk of heart attack, my risk of heart attack,
five-fold at high doses. The FDA waits two years before it, basically, does nothing, which is in a
small labelling change that has no effect.

JONATHAN HOLMES: Like Gurkirpal Singh, David Graham spends a lot of time these days in Senate
committee hearings. He's an expert on drug safety and the FDA's most prominent whistle blower.

DAVID GRAHAM: VIOXX is a terrible tragedy and a profound regulatory failure. I would argue that the
FDA, as currently configured, is incapable of protecting America against another VIOXX - we are
virtually defenceless.

JONATHAN HOLMES: In the mid '90s, the FDA was given extra resources to speed up its drug-approval
process, paid for by fees from the very industry it's supposed to police. That, says David Graham,
has made it a toothless watchdog.

DAVID GRAHAM: Industry money has brought about a culture shift within the Agency that now comes to
view industry as the client, as customer one. And what does it mean to have the industry as your
client? It means, "I represent their interests." And that is what the FDA is now in the position of
doing, representing the interests of the industry, over the interests of the American people.

JONATHAN HOLMES: The FDA maintains that it simply doesn't have sufficient power to be a tougher

DR SANDRA KWEDER: We don't have the authority to tell a company, "This is how your label has to
look, this is the language that needs to go into your label, here's where it goes, end of story."

JONATHAN HOLMES: The FDA refused to take part in this program. But the man who chaired its
independent expert panel on the COX-2 inhibitors eight weeks ago was more forthcoming. Indeed,
Professor Alistair Wood was surprisingly frank.

Isn't it an extraordinary situation that a regulator, faced with a drug which may well be causing
tens of thousands of deaths, should have to negotiate with the manufacturer for 18 months to get a
label change?

PROF ALASTAIR WOOD: It is. And it's unacceptable. And it reflects the environment in the United
States now, that - in which the FDA sees itself as a partner with industry. That part may be
appropriate. But at some point, you have to be a regulator and understand what your regulatory
imperatives and responsibilities are.

JONATHAN HOLMES: Australia'sTherapeutic Goods Administration denies it has similar problems, yet
financially it's more dependent, even, than the FDA, on pharmaceutical industry fees. Since the mid
'90s it's received no taxpayer funding at all.

Is it appropriate that the office that's responsible for the public safety should basically get all
its funding from the pharmaceutical companies themselves?

DR JOHN MCEWEN: As I've explained to you, that's a matter of government policy.

JONATHAN HOLMES: Are you happy with the government policy?

DR JOHN MCEWEN: I can't comment on government policy.

JONATHAN HOLMES: So let's look at the results. Like the FDA, the TGA received preliminary data
about the VIGOR trial in mid-2000. 18 months later, in January 2002, the product information for
VIOXX was updated. It was even less explicit than the new label in America would be. There are
pages on the gastrointestinal benefits of VIOXX. There's a single paragraph about cardiovascular
effects. It's far from hard-hitting. It says that in "a large clinical trial the rate of
cardiovascular thromboembolic events was significantly lower in patients with Naproxen than in the
VIOXX group. Physicians should assess the importance of these data for an individual patient at
risk for cardiovascularthrombo-embolic events." The new product information also warned doctors not
to prescribe more than 25mg of VIOXX per day. That's as much as the TGA could do, says its medical
director, without proof that Merck's Naproxen hypothesis was wrong.

DR JIM MCEWEN: You have to bear in mind that we're open to challenge all the way. I mean, if we
publish something, we could end up in a court for saying something that we can't support or is
untrue. I mean, we live in a very active environment. We have to be fair in our procedures and in
our judgments. And the issue is, was Naproxen protective or not? Now, if we have ...

JONATHAN HOLMES: Why wasn't the issue, is VIOXX dangerous or not?

DR JIM MCEWEN: If - we - in order to show, in order to show that VIOXX was dangerous, one had to
show that Naproxen was not protective, and those data did not exist at the time that VIGOR was

JONATHAN HOLMES: Don't you think that Merck basically snowed you, snowed the FDA, snowed the
medical community with this Naproxen tale?

DR JIM MCEWEN: I wouldn't use the word "snowed" because I'm not sure what that implies. I think
that Merck developed a strategy which was reflected in their dealings with us, which was to portray
this as being a protective, effective Naproxen and not a thrombotic effect of VIOXX and ...

JONATHAN HOLMES: Well, that was clearly a strategy that favoured their drug?


JONATHAN HOLMES: And you accepted it?

DR JIM MCEWEN: Well, one - as I've explained to you before, in order to challenge it we have to
have their data and to go through their data and then to say, "Do we have other data to say that
Naproxen is not protective?"

JONATHAN HOLMES: Critics argue that when they first saw the VIGOR results five years ago, the
regulators here and in America should have insisted that Merck conduct a large-scale safety trial.

DR ERIC TOPOL: That would've been the time to get this story straight, once and for all. But the
companies resisted that, they didn't want to go there. And it was very obvious why they didn't want
to go there -because they knew there was a potential liability.

JONATHAN HOLMES: But once a drug's been given market approval, even if it's been fast-tracked, the
regulators can't order the drug companies to do expensive clinical trials they don't want to do,
either in America or in Australia.

DR JIM MCEWEN: The FDA doesn't have the power to force those studies, and it's in dispute that we
would have the power to force those studies once a drug is on the market.

JONATHAN HOLMES: But, surely, if this thing teaches us anything, it's that you should have that?

DR JIM MCEWEN: Well, I think - we want to certainly put beyond dispute that we can condition
licences in the future. . .

JONATHAN HOLMES: But this has been taken by millions of Australians. If you had a suspicion that
some of them, hundreds of them, might've been being killed by this drug - I mean, you might've had
that suspicion - you should immediately be able to do something about it?

DR JIM MCEWEN: Yes, and we, in the proposed legislation, which will probably be enacted as part of
the formation of a trans-Tasman Australia and New Zealand regulatory agency, we'll seek that power,
we'll ask the Parliament to give us that power.

JONATHAN HOLMES: In the absence of clinical trials the TGA had to rely on so-called 'observational
studies' overseas. Researchers began plumbing through medical data banks to see how the
heart-attack rates of people on VIOXX compared with patients on Celebrex and other drugs. It's the
kind of study that Australia's tough privacy laws make it almost impossible to do here, to the
frustration of Australian researchers. So it was an American study in early 2003 which nudged the
TGA's Adverse Drug Reactions Committee, ADRAC, into action.

DR JOHN MCEWEN: On the basis of a study in Tennessee it appears that there is an increased risk of
cardiac events, of myocardial infarction and the like, with 50 mg. And it's not there with 25mg of
VIOXX, it's not there with Celebrex, it's not there with Naproxen and it's not there with
Diclofenac. The start of 2003, the world's experts pointing that out. We put out a message within
six months.

JONATHAN HOLMES: In October 2003, a year before the VIOXX recall, the TGA issued an ADRAC bulletin
about COX-2 inhibitors: "There may be an increased risk of cardiovascular and cerebrovascular
disease," with the COX-2s, it warned. VIOXX in particular: "Should not be used at doses exceeding
the maximum approved dose (25mg a day)." In fact, that had been the maximum approved dose in
Australia ever since VIOXX was put on the market. So how much difference the ADRAC bulletin made is
open to doubt.

It certainly didn't influence Ian Lewington's doctors. A sufferer from rheumatoid arthritis, he
took part in the VIGOR trial in Melbourne in 1999. Like everyone on VIOXX in that trial, he was on
50mg a day. And with the permission of the Health Insurance Commission his doctors kept him on that
dose, double the recommended maximum, for five years. In August last year, 10 months after the
ADRAC bulletin spelled out the dangers, Ian Lewington had a mild heart attack that put him in

You carried on, on VIOXX after that?


JONATHAN HOLMES: No-one suggested to you that taking 50mg of VIOXX every day for years might've had
something to do with that heart attack?

IAN LEWINGTON: No. No. No, I was happy with the drug. It was doing what I expected it to do and I
had no reason to query it anyway.

JONATHAN HOLMES: Trish Hunsley's heart attack, much more serious than Ian Lewington's, occurred a
few weeks before the ADRAC bulletin was issued. But she stayed on VIOXX for another seven months.

Did anyone in the hospital, when you'd had that heart attack, suggest that VIOXX might've had
anything to do with it?

TRISH HUNSLEY: No, they didn't, no.

JONATHAN HOLMES: Did they take you off VIOXX, or tell you not to go on taking it?

TRISH HUNSLEY: No, they didn't.

GP: Thank you very much.

JONATHAN HOLMES: The truth is, Merck was extraordinarily successful in keeping the debate about
cardiovascular side effects off the radar of busy GPs.

MUKESH HAIKERWAL: I often talk about the view that we're given as a rose-tinted glasses view. You
only get the good information, and that's magnified, as opposed to knowing what the potential
problems are.

DAVID GRAHAM: you and to the committee ...

JONATHAN HOLMES: One of the most disturbing examples of problems being downplayed was the
experience of David Graham with his bosses at the FDA.

DAVID GRAHAM: ... personally, I have great difficulty standing here before this committee and
remaining silent on things that I know about that I'm not allowed to talk to you about. Fortunately

JONATHAN HOLMES: In mid-2004 Dr Graham completed a study of VIOXX patients on a big Californian
medical database. The results were startling.

DAVID GRAHAM: There was about a three-and-a-half-fold increased risk with high doses of VIOXX, and
we found about a one-and-a-half-fold increased risk with lower doses of VIOXX.

JONATHAN HOLMES: It was exactly the sort of finding that dissidents like Dr Gurkirpal Singh had
been predicting. But Dr Graham's bosses at the FDA, he says, went ballistic.

DAVID GRAHAM: They didn't have a problem with the data. They had a problem with my conclusions. My
conclusions were that the high dose of VIOXX should be banned, and that the low dose of VIOXX was
less safe than Celebrex. I was severely pressured to change my conclusions, to water them down.

JONATHAN HOLMES: By the time they'd crossed the Pacific, Dr Graham's watered-down conclusions had
become mere murmurings.

MUKESH HAIHERWAL: There were murmurings right up until two weeks before the withdrawal of VIOXX in
October last year. There were potential complications. The manufacturer wrote individually to every
doctor, reassuring us that those were spurious concerns.

JONATHAN HOLMES: Merck's "dear, doctor" letter of September 7th dealt with David Graham's report
without naming it.

WOMAN: "You may have seen or heard media coverage this week of a story about the risk of heart
attack. Merck stands behind the efficacy, overall safety profile and cardiovascular safety profile
of VIOXX."

MUKESH HAIKERWAL: So it was quite a bolt out of the blue to see VIOXX being pulled in October last

NEWSREADER: We ask that anyone who is taking VIOXX stop doing so immediately and contact their

NEWSREADER: New data found a small percentage of patients may be at greater risk of heart attack or
stroke after taking the drug for more than 18 months.

JONATHAN HOLMES: The new data came from a trial whose main purpose was to extend the authorised
uses of VIOXX, but in this trial it was compared to a placebo. Even at 25mg a day, the evidence of
cardiovascular risk was undeniable. Merck put the best spin it could on its decision.

RAYMOND GILMARTIN: Given the availability of alternative therapies and the questions raised by the
data withdrawing VIOXX was consistent with an ethic that has driven Merck's actions and decisions
for more than 100 years. Merck puts patients first.

JONATHAN HOLMES: Since the Merck withdrawal, more evidence has emerged about COX-2 inhibitors as a
class. Last week in America, Pfizer's Bextra was withdrawn from the market. Celebrex and all the
non-steroidal anti-inflammatory drugs have been told to carry black-box warnings of cardiovascular
risk. In Australia the makers of Celebrex and Mobic are fighting a similar instruction by the TGA.
But there's no sign here of the fierce debate that's raging across the Pacific.

ERIC TOPOL: This is the worst prescription withdrawal in medical history. The largest number of
people who were affected with unintended harm. And so, we need to learn from this. We can't have
something like this happen again.

PROF ALASTAIR WOOD: We want to get drugs to patients that need them quickly. However, once we've
got the drug on the market, in that setting, particularly when we've approved it quickly ... we need
to insist at that time that there are appropriately sized studies that demonstrate the safety and
efficacy of the drug that are carried out and agreed to be carried out and that we check are
carried out after the drug gets on the market. When these studies show up problems, we need to be
prepared to act on them quickly at that time.

JONATHAN HOLMES: We're not doing that at the moment?

PROF ALASTAIR WOOD: We're not doing that at the moment.

JONATHAN HOLMES: As the population ages more and more Australians will take pills for years, to
stay alive or simply to make their lives more comfortable. Most drugs have side effects. Some are
revealed only over time. But as the VIOXX story shows, once a drug is approved, the balance of
power shifts from regulator to marketer. The time has surely come to shift it back.

DISCLAIMER: The organisation referred to in our program and on our website - Merck & Co., (US) and
Merck Sharp & Dohme (Australia) - has no relationship with any other organisation of similar name.