Book Review: The Drug Trial

WARS, EVEN THOSE FOUGHT on principle, are invariably sordid affairs. And so appears to have been the case with the all-out battle waged between Nancy Olivieri, a respected physician and scientist at Toronto's Hospital for Sick Children, and Apotex, one of Canada's biggest pharmaceutical companies.

Book Review: The Drug Trial

WARS, EVEN THOSE FOUGHT on principle, are invariably sordid affairs. And so appears to have been the case with the all-out battle waged between Nancy Olivieri, a respected physician and scientist at Toronto's Hospital for Sick Children, and Apotex, one of Canada's biggest pharmaceutical companies. Their fight over the safety and effectiveness of L1 - an experimental drug to help patients with thalassemia, a rare blood disorder - made international headlines in the late 1990s. To many, it seemed a clear-cut tale of a laboratory David taking on health industry Goliaths, as Olivieri struggled against threats of legal action, unsympathetic bosses and scornful colleagues to publicize her concerns. But a controversial new book - The Drug Trial by Miriam Shuchman, to be published on May 3 - suggests the science and ethics of the case were far more complex than most people believed. And that the doctor, who became one of Canada's most celebrated whistleblowers, unwittingly may have ended up hurting the people she was trying so hard to protect - thalassemia patients.

"I think there are people who would be alive if L1 had continued to be available in North America and had they stayed on it," Shuchman said in an interview. Though the reasons why are still unclear, her book reveals that thalassemia sufferers in Toronto have been dying in greater numbers over the past few years than those in the United Kingdom, Cyprus and Italy - places where the drug is still available and widely prescribed. (The difference in death rates may also be a result of problems with the way care is delivered in Ontario.) "Nancy Olivieri isn't the one who approves drugs in North America," says Shuchman - but the doctor's well-publicized struggle has helped shape the debate on this side of the Atlantic over L1's risks and benefits. "The way science works is problematic," Shuchman says. "Individual, influential scientists have too much say over what gets presented, published, and what gets attention. And that's what sways the regulatory agencies."

In the mid-1990s, Olivieri was overseeing a number of Apotex-funded clinical trials in Toronto and other cities when she became concerned that the drug might not be as effective as she had believed. (L1 is a product that helps remove excess iron in the heart and liver - a potentially fatal side effect of the frequent blood transfusions thalassemia patients must undergo. It remains the only oral alternative to the standard treatment, Desferal, a drug that is delivered via painful injections, and one that some patients have to stop taking because of discomfort and side effects.)

Other scientists disputed her conclusions, and as the battle escalated in the spring of 1996, the drug company pulled the plug on her Sick Kids' trial and threatened her with legal action if she shared her concerns with her patients or the public. Over the next two years, Olivieri's worries grew, and she became convinced that L1 was not just ineffective, but toxic, and was causing liver damage. In the summer of 1998, she published her findings in the New England Journal of Medicine, touching off a media frenzy.

Shuchman, a health journalist and MD who teaches medical ethics at the State University of New York at Buffalo, was one of the first to report on Olivieri's case. From the beginning, she has believed that Apotex was in the wrong. "They stopped the trial and they tried to shut her up," she says. "They cleared the drug out of the pharmacies and they said you can't talk about this under our confidentiality agreement. I don't have any sympathy for them." But as she delved deeper into the story, Shuchman also came to the conclusion that Olivieri's role and conduct in the debacle were less than exemplary.

The book traces the development of L1, and Olivieri's rise to international prominence as one of the chief proponents of the drug. Shuchman details a number of occasions when the scientist appeared to have discounted or ignored warnings from fellow researchers about the potential dangers of the treatment. In 1989, for example, a study found L1 to be toxic to mice, and a British patient taking the drug almost died after a precipitous drop in white blood cells left her susceptible to infections. The prestigious British medical journal The Lancet ran an editorial declaring the drug "too toxic for further development." But as Shuchman writes, those concerns were not mentioned in a grant proposal Olivieri submitted to Canada's Medical Research Council seeking money for a long-term study of the drug. Shuchman says she was surprised by her findings. "When the story of her battle with Apotex became public, Nancy said that patients should never get toxic drugs, and that it would be wrong to do that. It was as if she'd forgotten that she'd ever been involved in prescribing a toxic drug."

More troubling still is the unflattering portrait that Shuchman paints of Olivieri's interaction with her colleagues. She details an investigation that Sick Kids launched in 1992, following a spate of complaints from secretaries, nurses and medical residents about the doctor's rude and abusive behaviour. Patients, says Shuchman, sometimes referred to the mercurial physician as "their own Murphy Brown." Olivieri kept her job, but the book suggests she didn't mellow. As her international prominence grew, so did her difficulties with co-workers. Bewildered friends and underlings would suddenly find themselves cut off for no apparent reason. And the doctor levelled potentially career-ending allegations of misconduct against one former protege, charges that were ultimately found to be groundless. As a teacher, Shuchman says she found Olivieri's behaviour particularly troubling. "The notion that you could turn on those people who have no power over you - I don't understand that."

Shuchman's account of the L1 dispute is admittedly one-sided. Although their relationship was once cordial, Olivieri has not spoken to her since the summer of 2000, when she learned of Shuchman's intention to write the book, and on one occasion tried to have her removed from public meetings they were both attending. The doctor's many supporters will rightfully point to the book's heavy reliance on unnamed sources and anonymous quotes. Shuchman says this is because many of the people she interviewed were worried about being sued by Olivieri, who has in the past mounted a ferocious legal campaign to safeguard her reputation. Random House Canada, the book's publisher, is also clearly concerned, and on many occasions The Drug Trial reads like it was written by lawyers. The publishing house has also worked hard to prevent a pre-emptive legal strike - there has been little advance talk, and the book was purposely not listed in the Random House catalogue of spring offerings.

Olivieri, who won substantial legal settlements from Sick Kids and the University of Toronto, and who has been vindicated by investigations at the hospital, at the university level, and by an extensive inquiry by the Ontario College of Physicians and Surgeons, will presumably not be pleased by the book's brew of new, and old, allegations. But the fact remains that over the past few years, a number of other scientists have raised serious questions about the validity of her research showing L1 to be ineffective and dangerous. With thalassemia patients in North America still being denied access to a drug that many of them tried and favoured over existing treatments, Shuchman's book is sure to reignite the debate. Whistleblowers are often extraordinarily courageous people with the best of intentions. But there are dangers associated with putting anyone up on a pedestal.

See also PHARMACEUTICAL INDUSTRY.

Maclean's May 9, 2005