By Margaret Munro CanWest News Service
Four-year-old Ryan Lucio survived the first four drug overdoses. The last two killed him. Ryan’s liver, heart and lungs began to fail. He developed hallucinations and severe bleeding and died at an Ottawa hospital from an experimental drug administered at 25 times the correct dose.
The youngster from Sault Ste. Marie, Ont., had been diagnosed in early 2002 with neuroblastoma, a rare and deadly form of cancer. The cancer appeared to be in remission when his parents, Peter and Maria, learned their only child had been selected by doctors to participate in an international clinical trial underway at eight research centres across Canada.
They agreed to enrol Ryan in the Ottawa arm of the trial hoping the treatment would cure him.
Instead, Ryan’s death in September 2002 stands as a tragic reminder of how dangerous clinical research can be. And as a CanWest investigation has found, it illustrates how American health authorities are more likely to blow the whistle on scientific and ethical misconduct involving Canadian researchers than federal government agencies in this country.
U.S. health authorities were so concerned they sent an investigator to Ottawa to find out how things could have gone so terribly wrong with a trial funded by the prestigious U.S. National Cancer Institute.
Patricia Murphy, a U.S. Food and Drug Administration inspector, spent a week at the Children’s Hospital of Eastern Ontario in January 2003 combing through binders of notes kept on Ryan and the other youngsters who received the experimental interleukin-2 treatment.
“You failed to protect the rights, safety and welfare of subjects when you administered overdoses of the study drug interleukin-2 that were 22 to 25 times higher than the dose specified in the protocol,” the FDA said in a subsequent letter sent to Dr. Jacqueline Halton, lead investigator of the Ottawa arm of the trial.
The letter, dated April 14, 2003, goes on to say that “as a result of the overdoses” Ryan died and another child “suffered adverse events.” The child who survived received 22 times the correct dose during his first round of four treatments beginning July 23, 2002. He developed fever, lethargy and a skin rash so severe doctors discontinued his treatment, says the FDA warning letter.
But the Ottawa researchers, who had grossly miscalculated how much drug to give their young charges, failed to realize their error. When Ryan arrived at the hospital six weeks later, they again miscalculated the dose, this time with deadly consequences.
The FDA has posted the warning letter to Dr. Halton on its website, where it sits in sharp contrast to Health Canada’s muted response to Ryan’s death and the problems associated with the trial.
“I am startled by the lack of reaction by Health Canada,” says Prof. Jocelyn Downie, director of the Health Law Institute at Dalhousie University, whose view is echoed by many of her colleagues.
“I think, in this case, the use of jackboots was warranted,” says Dr. Douglas Kinsella, retired assistant dean of medical bioethics at the University of Calgary who consults on ethics and clinical research. Ryan survived the first round of four treatments, all of them 25 times the correct dose, though he too developed a rash and fever, the FDA letter says. The side-effects subsided before Ryan returned to the hospital for the second round of two more treatments. This time, the FDA reports, Ryan’s major organs began to fail and he developed hallucinations and such severe internal bleeding that he died Sept. 30.
Murphy also noted other problems with the trial. The Ottawa doctors had failed to properly record a three-day hospitalization, in May 2002, of a young girl in the trial. The researchers were months late in submitting data on patient treatment to the study operation centre in the U.S. And the Ottawa researchers “failed to ensure” the experimental cancer drugs were stored at the right temperature to maintain “their specified characteristics.”
Health Canada officials are still reluctant to discuss the situation and would only answer queries for this story through Krista Apse, a media relations officer. But the department confirms that Ryan’s trial and seven related cancer trials across Canada were, through much of 2002, violating Health Canada regulations that require federal approval of trials before they can begin.
Department officials learned in March 2002 – seven months before Ryan’s death – that the trials “had not been authorized by Health Canada,” Apse says. Departmental officials discussed stopping the trials but allowed them to continue, since the trials had been reviewed and approved by U.S. authorities. But they urged the Canadian researchers to quickly complete the Canadian approval process.
Health Canada officials fired off a letter on March 20, 2002, to Dr. Mark Bernstein, a children’s cancer specialist at Ste. Justine Hospital in Montreal, who was representing the Canadian researchers running the unauthorized trials. It advised Bernstein the eight trials were violating the Food and Drug Regulations and asked him to file the necessary clinical trial application within four to eight weeks.
Bernstein failed to meet the deadline but did finally deliver the application on July 24. It was missing what Health Canada describes as “critical information” about the drug being tested on the children. Memos between Health Canada officials and Bernstein continued through the summer of 2002, which is when the first overdose occurred.
Under Health Canada regulations, investigators must report serious unexpected adverse reactions to the department in a bid to catch problems with experimental drugs early. The Ottawa doctors did not report the fever, lethargy and a skin rash the first child developed, Apse says, because the child’s reaction was “initially interpreted as a normally expected side-effect”. The doctors running the trials did, however, consult among themselves and decided to discontinue the child’s treatment, according to the FDA report.
The Ottawa research team made an even worse medication error – 25 times the correct dose – when Ryan Lucio arrived for his treatment Sept. 16. On Friday Oct. 4, Health Canada learned Ryan had died. That same day officials found out the Children’s Oncology Group had “activated ” more clinical trials, once again without submitting applications to Health Canada for approval.
Health officials decided, seven months after learning of the group’s first set of unauthorized trials, to have a “face-to-face meeting” with the cancer researchers.
The following week details of Ryan’s overdose and death were made public in an emotional press conference by doctors at the children’s hospital, who took full responsibility for his tragic overdose. No mention was made that the trial was violating Health Canada regulations.
Health Canada officials will not name the doctors or identify the other seven Canadian hospitals that ran unauthorized trials. Nor will it say how many children were enrolled in the trials.
Ryan’s parents have declined interview requests. So has Dr. Halton. Luce Lavoie, public affairs officer at Children’s Hospital of Eastern Ontario, said she believes cancer researchers in Calgary and Montreal were among those involved in the the interleukin trial.
After Ryan’s death the doctors involved in the cancer trials requested “provisional clinical trial approval” for the trials , Health Canada documents say. The department refused.
Apse says Health Canada officials did meet with the cancer researchers after Ryan’s death. She says the doctors suspended enrolment of patients in the unauthorized trials “of their own accord” while completing the long-overdue authorization process. The trials were finally authorized Oct. 25, 2002, more than seven months after they started and a month after Ryan died.
Health Canada says it saw no need to send an investigator to the hospital located a short drive from the department’s Ottawa headquarters. On-site inspection “was not deemed necessary,” as the children ‘s hospital supplied all the information needed by e-mail, fax and telephone, says Apse.
Dr. Bernstein and the co-chairs of the Children’s Oncology Group, which helps co-ordinate the trials – Dr. Max Coppes, director of the children’s cancer program at Alberta’s Children’s Hospital in Calgary and Dr. Victor Blanchette, chief of hematology and oncology at the Hospital for Sick Children in Toronto – declined requests for interviews. But in e-mails, Bernstein and Coppes suggested trials undergo a rigorous approval process in the U.S. and indicated that more approvals by Health Canada delays trials.
“We strongly believe that COG clinical trials need to be available to Canadian children without undue delay,” Coppes said in an e-mail.
“Other jurisdictions, such as New Zealand and Australia, allow for mutual recognition of multinational studies that have been reviewed by competent authorities such as the U.S. Food and Drug Administration and the Cancer Treatment and Evaluation Program without requiring further review,” writes Bernstein. Downie disagrees. “We have different standards than the Americans,” she says. Standards that she says Health Canada should be much more proactive about enforcing.
By letting the cancer researchers break the rules for so long, Downie says Health Canada sent a message to the research community that “not much happens if you don’t comply.”
Health Canada says it did send a letter to research centres, drug companies, research ethics boards, and hospitals across Canada after Ryan’s death reminding them that clinical trial applications must be filed with Health Canada. Compliance with the regulations “is obligatory,” assistant deputy health minister Diane Gorman said in the letter.
It made no reference to the way Canada’s cancer researchers had for months knowingly violating the federal regulations. Nor did it.