Drug Trials Controversy

Drug Trials Controversy

By enduring frequent blood transfusions and painful injections that allow a drug to be pumped into her body at night, 14-year-old Julie Vizza has survived a rare blood disease called thalassemia that leaves her body dangerously short of oxygen. Today, she goes to school near her family home in Courtice, Ont., 30 km east of Toronto, and lives a "fairly normal life," says her mother, Anna Vizza. But, adds Vizza, because of the injections, "Julie has known pain from Day 1." In 1992, the Vizzas were filled with hope when Dr. Nancy Olivieri of Toronto's highly regarded Hospital for Sick Children launched a clinical trial to test a new thalassemia drug called deferiprone that is taken in tablet form. Although Julie was enrolled in a trial group that continued, for comparison purposes, to use an older drug, the Vizzas prayed deferiprone would prove safe and effective. "We had so much hope," recalls Vizza.

But Olivieri's study ended in disarray in 1996, initiating a bitter dispute that became public last August, involving charges of improper pressure by the Toronto-based drug firm Apotex Inc., alleged errors by Olivieri and accusations that Sick Kids', as the hospital is commonly known, failed to support the researcher in her acrimonious dealings with Apotex after she questioned the drug's effectiveness and safety. In turn, that dispute focused attention on the larger issue of whether researchers may be increasingly vulnerable to pharmaceutical company pressures as that industry invests more money in drug trials.

Last week, a 153-page report by Dr. Arnold Naimark, the University of Manitoba medical professor appointed by the hospital to lead an investigation into the disagreements, fuelled new controversy. While criticizing the hospital on several counts, Naimark said that Olivieri failed to inform hospital authorities about evidence of liver damage in some patients who were taking deferiprone. "I am not suggesting," Naimark told reporters, "that patients were necessarily at risk. But there was a process breakdown here." The next day, flanked by supporters at her own news conference, Olivieri said that she promptly informed patients and Apotex about evidence of liver damage in some patients and dismissed Naimark's commentary as "openly and unabashedly biased."

In fact, Naimark's cautiously worded report backed Olivieri on some key issues. Although senior hospital officials told Naimark that they intervened with Apotex on Olivieri's behalf, Naimark criticized the institution for not supporting her publicly - Olivieri and her colleagues, he said, "lacked the comfort of knowing that the hospital was behind them." And while he faulted Olivieri for signing a research contract with Apotex that barred her from revealing findings without the company's permission, Naimark also criticized Sick Kids' for not enforcing a requirement that such contracts be made known to hospital authorities. "I'm not exonerating the hospital of anything," said Naimark. "Its policy infrastructure was weak."

On the issue of patient safety, Naimark's account was at odds with that of Olivieri, who boycotted his investigation because she considered him biased. Her relations with Apotex - which controls the rights to deferiprone - began to deteriorate in March, 1996, after she questioned the drug's effectiveness. Apotex disputed her findings and, in May, 1996, cancelled her portion of the trials, which are continuing internationally. Later in the same year, Olivieri began to fear that deferiprone might cause liver damage in some thalassemia patients. In Naimark's account, when evidence of liver damage in some patients emerged, Olivieri did not immediately inform the hospital authorities of her concerns - the hospital's ethics board only learned of them in February, 1997, after an Apotex official told the hospital. "It is generally felt," said Naimark, "that the obligation to report to the hospital's ethics board supersedes all other obligations."

But according to Olivieri, by the time doctors saw evidence of liver damage, the Apotex-sponsored clinical trial had ended at Sick Kids', although some patients were being treated under a Health Canada program allowing experimental drugs to be used in individual cases. That, she said, meant there was no longer an obligation to inform the ethics board. After tests confirmed some cases of liver damage early in 1997, she added, she warned patients of the risks at a Feb. 4 meeting. But some patients continued to use the drug after a senior Apotex official told them the liver damage findings were not correct.

In his report, Naimark noted that the Olivieri affair erupted at a time when government funding for medical research is in steep decline, leaving medical investigators increasingly dependent on pharmaceutical industry support. To prevent similar disputes in the future, said Naimark, research institutions need to have agreements with drug companies on ways of resolving disputes before entering into contracts. Meanwhile, trials involving deferiprone continue in Italy and the United States. "We have 500 patients who are surviving on this drug," says Apotex spokesman Elie Batito, "and we've got one person who's saying, 'You guys are wrong - I'm right.' " For Dr. Alan Cohen, a Philadelphia physician who is treating nine patients with deferiprone, the question of possible side-effects is one that, he says, "requires continued investigation and monitoring."

Maclean's December 21, 1998