CANADA: Fourth In A Series: Research Turns Deadly
Four-year-old Ryan died at an Ottawa hospital from an experimental drug given at 25 times the proper dose

Margaret Munro
CanWest News Service

February 26, 2004

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 began bleeding severely and hallucinating. He died at an Ottawa
hospital, two weeks after starting treatment with an experimental drug which was administered at 25 times the correct
dose.

The little boy from Sault Ste. Marie 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 on Sept. 30, 2002, stands as a tragic reminder of how dangerous clinical research can be. And, as
a CanWest investigation has found, it illustrates how U.S. health authorities are more likely than Canadian agencies to
blow the whistle on scientific and ethical misconduct involving Canadian researchers.

"I am startled by the lack of reaction by Health Canada," says Professor Jocelyn Downie, director of the Health Law
Institute at Dalhousie University, whose view is echoed by many of her colleagues.

U.S. health authorities, on the other hand, were so concerned they sent an investigator to Ottawa in January, 2003, 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 children who received the
experimental interleukin-2 treatment.

Her conclusion, summarized in a letter sent by the FDA to the lead Ottawa investigator, Dr. Jacqueline Halton, was
devastating:

"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 letter, dated April 14, 2003, goes on to say Ryan died "as a result of the overdoses," and another child "suffered
adverse events."

The other child, who became ill from the treatments but ultimately survived, might have served as a warning to the
Ottawa researchers that something was terribly wrong. After receiving 22 times the correct dose during his first round
of four treatments beginning on July 23, 2002, the boy became feverish and lethargic and developed a skin rash so
severe doctors discontinued his treatment, the FDA notes.

But the Ottawa doctors, 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, the
consequences were deadly.

After completing its investigation, the FDA posted the letter castigating Dr. Halton on its Web site; an unusual move.

In contrast, Health Canada has said virtually nothing about the death on its home turf. Nor did it conduct its own on-
site investigation. Indeed, Health Canada officials are reluctant to discuss the case at all. They would only answer
queries for this story through Krista Apse, a media relations officer. But Health Canada confirms Ryan's trial and
seven related cancer trials across Canada were, through much of 2002, violating its 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," Ms. Apse says.

Officials discussed stopping the trials but ultimately allowed them to continue, since the trials had been reviewed and
approved by U.S. authorities. Still, 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 Dr. Bernstein the eight trial centres were violating federal regulations and asked him to file the necessary
clinical trial application within four to eight weeks.

Dr. 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 Dr. 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, Ms. 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.

Then the Ottawa researchers made their lethal errors.

On Friday, Oct. 4, Health Canada learned Ryan had died. That same day, officials found out the same group of cancer
researchers had "activated" more clinical trials, once again without submitting applications to Health Canada for
approval.

Health officials decided then, 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 news 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.

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.

Ms. 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 on 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, Ms. Apse says.

Dr. Bernstein and the co-chairs of the Children's Oncology Group (COG), 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, Dr. Bernstein and Dr. Coppes suggested trials undergo a rigorous approval process in the
United States and indicated more approvals by Health Canada delays trials.

"We strongly believe that COG clinical trials need to be available to Canadian children without undue delay," Dr.
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," Dr. Bernstein writes.

The researchers may be making a valid point that Canadian rules should be changed, but it does not excuse their
decision not to comply with existing rules. Moreover, Prof. Downie thinks Health Canada has made a big mistake in
failing to enforce its own rules.

By letting the cancer researchers break the rules for so long, Prof. Downie says, Health Canada sent a message to the
research community that "not much happens if you don't comply."

Fourth in a Series; Tomorrow: Rubber-stamping medical trials.

SOURCE: The National Post, Canada
http://tinyurl.com/2rosh

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