ABC TV report into the Vioxx controversy

[Guest guest]

(This caused a HUGE broohaha after airing this week on Aus TV)

Australian Broadcasting Corporation

FOUR CORNERS

Investigative TV journalism at its best.

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 The drug, Vioxx, has been withdrawn from sale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?

TRISH HUNSLEY: No.

JONATHAN HOLMES: And no pain?

TRISH HUNSLEY: No. No.

JONATHAN HOLMES: So that was great?

TRISH HUNSLEY: Yes, yes.

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. 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 strokes.

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 ulcers.

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 inhibitor.

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 wallets.

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 benefit.

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, ,

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 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?

MUKESH HAIKERWAL: Absolutely.

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?

DR DAVID BORENSTEIN: Yes.

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 Celebrex.

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 '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 - .

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 possibility.

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 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 attack.

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?

JIM ALBRIGHT: No, no.

JONATHAN HOLMES: Never discussed the fact that it might have

contributed?

JIM ALBRIGHT: No.

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, 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 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 regulator.

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

published.

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?

DR JIM MCEWEN: Yes.

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 hospital.

You carried on, on VIOXX after that?

IAN LEWINGTON: Yes.

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: …to you and to the committee …

JONATHAN HOLMES: One of the most disturbing examples of problems

being downplayed was the experience of 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 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 year.

NEWSREADER: We ask that anyone who is taking VIOXX stop doing so

immediately and contact their doctor.

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.