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Doctor Who Says 'Drug May Kill' is Dismissed

A dispute between a pharmaceutical company and a medical researcher over a new drug has sparked a fierce battle. Already it has led to lawsuits, gags, firings, hate mail and claims of intimidation.

A drug called deferiprone has just been approved in Britain. You will not know its name, nor that of the relatively rare blood disorder it treats. But in America and Canada this drug is known for something else. It is not licensed here and perhaps never will be. For a war has broken out over this drug in North America: on one side is the pharmaceutical company Apotex, on the other is the professor and medical researcher Dr Nancy Olivieri. The battle has never been violent but it is certainly nasty with lawsuits, gags, firings, hate mail, intimidation, and serious accusations all round.

The battle between Apotex and Dr Olivieri has been raging since 1995 when Olivieri said that she believed her clinical trial into deferiprone was showing the drug to be potentially dangerous to some patients. The company thought she was wrong and found others who agreed with it. It tried to control the data and her too. Dr Olivieri refused. She would not be controlled.

Apotex sees this as a case about science. It says the drug is safe and life-saving and cites many studies to support this view. However, Dr Olivieri can also cite studies to support her point of view. The decision, for Europe at least, will be made by the courts. Dr Olivieri's appeal to the Court of the First Instance in Luxembourg is to be heard in the next few months. She wants approval of the drug revoked.

At the core of this story lies not science but conflict of interest. This has become pernicious in the pharmaceutical world, and not just in North America. In Britian two-thirds of the people who sit on the Government's board which licenses new medicines have financial ties to pharmaceutical companies. In the list of interests, contained in last year's Committee on Safety of Medicines annual report, one professor alone lists links with 28 different drug companies.

Thalassaemia is a genetic blood disease which affects millions around the world, mainly in China, South-East Asia and India. In the West there are far fewer with the disease: the usual numbers given are 400 in Canada, 1,000 in America and 10,000 throughout Europe (there are about 790 in Britain). Many people with the disease in the developing world continue to go untreated.

People with thalassaemia cannot make haemoglobin, which is the oxygen-carrying pigment in red blood cells, and they must receive regular blood transfusions from their first year of life. The transfusions cause iron to build up in the body, however, which brings its own set of problems. Iron overload can lead to sterility, diabetes, liver failure and heart failure. If untreated, patients would typically die in their early twenties.

The breakthrough in thalassaemia came in the Seventies with the drug deferoxamine. It removes iron and was (and is) universally seen as safe. However, the only effective way to administer it is by long infusion. In practice this means it is pumped into the body for a period of six to eight hours at night. This is done at least five nights a week.

According to the details of the dispute published in the Times of London The Toronto Hospital for Sick Children, a teaching hospital that is part of the University of Toronto, has the biggest thalassaemia programme in North America. In 1986, Nancy Olivieri came to the hospital to take a staff job as a haematologist and research the disease. Soon afterward she read an article in a British journal about a new drug called deferiprone that removed iron build-up. It was a pill and, since its chemical make-up was given, she asked the university chemist to make it up.

She applied for a trial and this took place at Sick Kids, as the hospital is often called, from 1988 to 1993. In 1991 Olivieri went to the Food and Drug Administration in America - viewed as the best drug regulator in the world - to ask how to get the drug licensed. She was told more clinical trials were needed and that a drug manufacturer had to be involved. "They said I had gone as far as I could as an independent investigator. Where am I going to make it, my bathtub?" she asks. This is where Apotex comes in. It is based in Toronto and has close links with the university, which is the alma mater of its founder Barry Sherman. Until this point, Apotex had made only generic drugs. This was to be its first new drug. It agreed to help fund the long-term study and provide at least partial funding for two new studies: one in Toronto, another in Italy.

Dr Olivieri was involved in all three - she was in charge of the trials in Canada and a paid consultant for the Italian trial. She did not receive money directly for overseeing the Toronto trials, but signed research contracts that stipulated controls on her data. Apotex says the total money required for the trials and attached costs was about two million Canadian dollars.

At first, the data looked promising and, in 1995, Olivieri published a research paper in the prestigious New England Journal of Medicine that said as much. However, subsequent results worried her. The iron load in some patients was going back up. When the trend continued, she decided that she wanted to tell the patients.

Apotex disagreed with her interpretation of the data and Olivieri sought advice from the chairman of the hospital Research Ethics Board. He agreed with her concerns and asked her to revise the consent forms for patients. "I sent them on May 21, 1996, which is a Tuesday, and on Friday I returned to my office about 4 o'clock and found two letters," she says. They were from Dr Michael Spino, a senior vice-president at Apotex. "One said the trial is cancelled and the drug will be taken out of the pharmacy immediately. The second removed me from the Italy trial." The letter also said the patients should not be told. A similar instruction was left on her answering-machine tape.

The battle had begun and, when you hear about it now, it sounds like one of those cat-and-mouse cartoon chases, albeit one with a very serious theme. Olivieri would give her results at a conference and someone from Apotex would stand up and challenge her. The university set up a committee to investigate, but Olivieri said too many of its members had links with drug companies. The hospital tried to fire her, but she was reinstated after the intervention of some of the most eminent scientists in the field, including Sir David Weatherall and Professor David Nathan of Harvard University.

In 1998, she did something that would be seen as unforgivable by her critics: she published a research paper on the drug's toxicity in the New England Journal of Medicine. She says that at least five of 14 evaluable patients, or 36 per cent, had suffered under the drug. The publication split the doctors and scientists at the hospital and, in late 1998, a poison pen letter campaign began.

The letters were sent to the four doctors at the hospital who had never wavered in supporting Olivieri. (She calls them the "Gang of Four".) Peter Durie received four letters and one included the line: "How did you ever get yourself in the middle of this group of pigs. Or did you think that their shit would not touch you?" He was a "foul air balloon" who should leave the hospital. Olivieri says that a different letter, sent to the press, attacked her personally and said she was promiscuous.

The Gang of Four thought they knew who was sending the letters. Dr Gideon Koren, a distinguished researcher at the hospital, was the other investigator on the 1993 Apotex trial, but he disagreed with Dr Olivieri's conclusions. Plus the spelling in the letters was appalling and this was known to be a problem for Dr Koren, whose first language is Yiddish.

The gang thought the hospital's investigation was marooned and so they hired a private investigator, a linguistic expert and a document analyst. The letters were found to be all typed on one machine and by one person. Dr Koren was adamant it wasn't him.

Then one of the gang came into a bit of money and decided to spend it on DNA analysis. Another ally, Dr Michelle Brill Edwards, suddenly remembered that she had received a letter from Dr Koren with a job offer. She produced both letter and envelope. It was only when the DNA matched - irrefutable evidence and dramatic enough for any Hollywood film - that Koren admitted his guilt. The hospital declared that Dr Koren was too valuable to lose, though he has resigned from several of his posts. He was suspended for six months until June this year; two months were without pay.

Dr Olivieri may look slight and almost ethereal with her halo of blonde curly hair, but she says she is tough and I believe her. "That I'm still here is probably the most important thing of all," she says.

She is still in charge of the thalassaemia and related programmes there. The European case now takes a lot of her time, as do various lawsuits involving claims and counterclaims about honesty and misinformation. "The only way to ensure your job, as people have found here, is to speak out. The quiet people are the ones who get cut."

Dr Olivieri regrets nothing, but says she has been on a learning curve that is steeper than a toddler's. "Did you ever read the Regeneration trilogy?" she asks. These are books by Pat Barker about the First World War. "It's about boys who came from the Front. It says: I was at the Front and the people who were at the Front with me, well, nobody else really matters. I look at people around here and think, 'He fired me, or, oh, he sided with Koren'. Then I see Peter Durie and say: 'Do you want me to die for you today?' That's what I would do for those people. There are only 10 people in the world like that but they were enough. They are in this on a daily basis."

But isn't she tired of it all? Doesn't she yearn to get back to normal? "I don't think it will be back to normal, but maybe that's a good thing." If she wins any of her suits, she wants to campaign to change the way drugs are regulated in Canada. "I'll try to imitate what Ralph Nader did. He changed things."

Research, she says, no longer attracts her. "I know now that if I found the drug tomorrow that cured cancer and the drug company didn't like the result, that it wouldn't matter . . . I know now that I work in the world where only 10 per cent of people really matter. The others can all be bought. They can rationalise it." She adds: "I don't think any of us could do this fight again."

MICHELLE BRILL EDWARDS is like a breath of fresh air in this debate. We meet at 8pm after a long day's work for her at the thalassaemia clinic at Toronto General Hospital, which is just across the street from Sick Kids. She is as relaxed as Nancy Olivieri is intense and immediately puts into perspective why everything seems so personal in this story. It's because it is personal. Almost everyone involved worked at Sick Kids or has received funding of some kind from Apotex.

She explains that Dr Michael Spino used to be a professor and work at the hospital before he went to Apotex - and that to this day he retains that position (unpaid) and supervises graduate students at the hospital. "Everywhere you look there is conflict of interest. Everywhere. If we drew a diagram of each person and all their connections . . ." Her right hand starts to circle wildly in front of her. "Well it would be very hard."

She is an expert on drug regulation in Canada, having spent some years on the drug regulating body, and believes people confuse the idea of conflict of interest with dishonesty. "The moment you raise this issue, people react with indignation and accuse you of saying the person is dishonest. But you are not."

She says it is like trying to judge a contest in which your own daughter is taking part. "Because of my special relationship with my daughter, my judgment on this might be skewed. I won't be indifferent to each candidate similarly."

Research money provided by a drug company always carries a potential conflict, says Dr Brill Edwards. Does she mean that researchers will produce results the company wants? "It's not as blunt as you put it. It's far more sophisticated."

Nobody will ever say that two plus two equals five, she says. "The argument will be as to whether it is really four or 4.1, because 4.1 is so close to four that couldn't we just say it is as good as four?" I say that, in the Olivieri case, there are so many studies cited that it is confusing. She nods, munching away at the muffin that is her dinner. "But that is classic. This is an industry that knows that the field is so confusing that as long as you controversialise something, you can get away with anything."

She points to the door of her office. "See that door. We both agree that is a door but if I'm a lawyer for a drug company, well, that could be something else."

What? "A window for example."

What? "Well, there is a frame and if that was glass, then it would look like a window and would serve the same purpose as a window. And, pretty soon, even though we know it is a door, we would be dealing with a controversial door. And once something is controversial, everybody starts to think there must be something to this, or it wouldn't have got this far."

IF YOU figure in the windchill, it is 22 degrees below zero when I arrive at Apotex's headquarters in northwest Toronto. It is a large building with a glass front and a shiny steel A over the front door. Inside, the boardroom is large and one wall is covered by an old Masters-style painting of apothecary flasks. It is warm inside but, by the time the interview ends, the atmosphere is icy and that's without windchill.

The main reason for this is that the company - and particularly Dr Spino - believe I have been duped by Nancy Olivieri. They suspect that The Times has been "targeted" by her. About two-thirds of the way through, medical adviser Dr Fernando Tricta says I am clearly not interested in the drug itself, or the patients, and walks out of the interview. "This is not a lifestyle drug, it is a life drug," adds Elie Betito, the company's director of public and government affairs.

They say Apotex got involved with the deferiprone trials as an act of goodwill. "You see that was my academic streak talking," says Dr Spino. "It was stupidity. Never should have done it. No smart company would have done it. Why invest in something that has no return?" Perhaps, I say, because it would be profitable in the future? He thinks not. The company is only promoting it as a second line therapy - ie, for people who cannot use deferoxamine - and the actual number of patients in the developed world is less than 12,000. What about the Third World? Dr Spino shakes his head. "Right now in China there are a lot of thalassaemia patients. But they don't even get transfused. They just die."

By now Dr Spino is striding round the room. He has rolled up the Old Master-style painting to reveal a blackboard and is writing numbers of cases on it in full professorial mode. "I am saying that nobody - NOBODY- develops a drug for this."

I ask about conflict of interest. There are persistent reports that Apotex was going to give the university $20 million (£10 million) but withdrew after the Olivieri controversy arose. They say that there was an earlier grant for $5 million to the hospital that was totally unconnected. And the idea of a $20 million donation was withdrawn for financial reasons within the company that, again, were not connected to the Olivieri case.

Did Dr Spino feel his professorship was a conflict of interest? "Do you have a conflict of interest in this story?" he demands. "Are you trying to sensationalise this so that you can sell more newspapers?" No, I say.

"So why can't my research be based on research I'm trying to do as opposed to generating money?" I say that he chose to go into industry and some would see that as a conflict of interest. After all, he was a professor at the university which was conducting trials for his company's drug.

"I don't see the point. How many people in academia today do you think are not involved in industry in the biomedical field? Anybody who is any good is."

But is there is a conflict of interest for doctors whose research is funded by Apotex? "You are impugning anybody's reputation because they have had some funding from the company. That's what Nancy has succeeded in doing. She is saying if you've been funded, you have been impugned. That's not right. You are saying that people are going to sell their reputation for a shekel. I know some people will." But, he says, that there is no way that the many people involved in this case would sell their professional souls. "You cannot impugn these people because they have had some funding. That's horrible. That's consistent with saying - though I'm now starting to believe it - that you are going to write this for sensationalism because you will sell more papers."

He is adamant that this story is not about a whistle-blower who was gagged. It is a story about a scientist whose interpretation of the data was wrong.

So, I ask, should Apotex have dealt with it differently? Did he see how bad it looked? "We didn't do this for looks. We did this because somebody was saying something that could not be justified on the basis of the data. It wasn't just us saying this . . . So what do you do? Do you let a person who is misrepresenting our information continue?" Well, I say, the world would say that she should be allowed to publish her point of view.

"Without any other side?" he asks. "Just her side? Or does the other side get a chance?" Well, I say, it's science.

"It's not her data." What does he mean? "It's our data. It's quite clear. Every single contract that is done with any industry, the industry owns the data. So it's our data, it's not her data." Dr Spino says I am asking the wrong questions. I am concentrating on the past. I am asking "Nancy" questions. I'm not talking to the patients. I need to talk to doctors involved in certain studies. I need to see how patients are living, not dying. I need to look at Europe, where he is sure Olivieri will lose her case. He talks about other studies that look very promising for the drug, so much so that it might become a first-line therapy. So, I ask, why not stop all this talk of the past for good by rerunning the Olivieri study? "But that's another Nancy perspective. And that's already been done." She would say it hasn't. "Well, I don't care."

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