Promoting openness and full disclosure
www.ahrp.org
FYI
The Canadian CanWest News Service is running an investigative series of
reports revealing that Canadian medical institutions, such as the
University of British Columbia, have been violating safety requirements for years,
conducing unethical, harmful medical experiments involving human
subjects-including children.
One casualty of Canada's failed regulatory and oversight system was a
four-year-old child who died from an experimental drug that was
administered in mega doses:
"Ryan's death on Sept. 30, 2002, stands as a tragic reminder of how
dangerous clinical research can be."
CanWest reports that 523 projects, funded variously by industry, non-profit
agencies and Canadian and U.S. government agencies, and involving
treatments for everything from dementia to cancer, were not properly approved before
they went ahead.
As the documents on the AHRP website demonstrate, lax enforcement of
safeguards for human research subjects is pervasive in US medical
institutions. Sadly, Canadian medical centers seem to be following the
trend of putting the interests of those who have a financial stake in research
ahead of the safety of patients. The bio-tech industry, medical research
centers and the scientists all have vested commercial interests that often
conflict with patient best interest.
Another recent example of a research casualty is Traci Johnson, a
previouslyhealthy, normal,
19-year old student who volunteered for an Eli Lilly antidepressant drug
experiment. The student was given high doses of Cymbalta (duloxetine), an
experimental drug--she committed suicide. Lilly disavows responsibility,
affecting a "business as usual" attitude, as it focuses on the projected
profits from Cymbalta. This is a perfect example of the corporate culture
that has invaded medicine.
See: GARDINER HARRIS, Despite Missteps, Eli Lilly Is a Hard Stock to Bet
Against, The New York Times, February 25, 2004, online at:
Here
All too often, the greater danger for patients who enroll in a clinical
trial, comes not from their disease, but from harmful, inadequately
reviewed or monitored medical experiments and an unreliable, faulty oversight system
that lacks accountability.
Contact: Vera Hassner Sharav
Tel: 212-595-8974
e-mail: [email protected]
CanWest News Service
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
Thursday, 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 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.
� National Post 2004
CanWest News Service
UBC broke drug-trial rules for years, documents show
Margaret Munro
February 25, 2004
UBC Hospital was among research centres reviewed.
The University of B.C. for years broke federal ethics rules and failed to
warn patients of all the dangers and side-effects associated with its
medical experiments and drug trials, CanWest News Service has learned.
Federal officials were so concerned about the breach, which was not fully
resolved until late last year, they threatened to freeze funding and
suspend patient enrolment for many of the affected projects at UBC and its
affiliated hospitals, according to documents obtained in response to an
Access to Information request.
In all, 523 projects, funded variously by industry, non-profit agencies and
Canadian and U.S. government agencies, and involving treatments for
everything from dementia to cancer, were not properly approved before they
went ahead.
The federal agencies now say they are satisfied that UBC "recognized the
significance of the breach," and in the end no trials -- most of them in
the faculty of medicine -- were shut down.
But officials at the Canadian Institutes of Health Research (CIHR) and the
Natural Sciences and Engineering Research Council (NSERC), the country's
two largest research-funding agencies, were so concerned when they learned of
the problem they threatened to freeze funding for the 44 projects they were
financing if UBC did not respond to their concerns "within two weeks."
Meanwhile, Health Canada was pressing UBC to quickly review projects
involving new drugs, most of which were industry funded.
"Should this review not be conducted, Health Canada will be required to
contact clinical trial sponsors to stop further enrolment in the approved
trials at the UBC clinical trial site," Dr. Robert Peterson, a Health
Canada official, told UBC on May 21, 2002. He gave the university six weeks to
complete the reviews.
UBC had discovered a year earlier, in May 2001, its research ethics board
had been cutting corners for years, but did not notify Ottawa for 10
months. The board, which must approve projects before they can start, tended to
only look at brief project summaries.
The practice violated federal rules that say ethics boards must review
detailed project protocols, which can run for more than 100 pages. The
protocols are considered key because they often reveal problems with
experiments and risks for patients.
Dr. Indira Samarasekera, UBC vice-president of research, said in a recent
interview the university acted quickly once the problem was discovered. It
revamped its ethics review process and dug out the full protocols to
determine if any risks had been missed.
She says she waited 10 months to inform then- health minister Anne McLellan
because it took time to determine how many projects had not been properly
reviewed. Federal officials didn't buy it.
"Although I acknowledge that the workload must have been huge, the argument
for not informing us earlier is not convincing," NSERC official Isabelle
Blain wrote in an e-mail to colleagues at CIHR shortly after Samarasekera
informed McLellan of the breach.
Samarasekera says in the end only 399 trials needed to be re-reviewed for
risks -- "side-effects like a headache or a rash," she said. No studies had
to be cancelled. But consent forms needed to be amended in 37 studies. In
only two cases did patients have to be "reconsented," says Samarasekera,
who
said she did not know the specifics of the two cases.
Of the 399 projects re-reviewed, 215 were deemed to have "potential ethical
issues." The most common problem, found in 126 studies, was "missed risks."
Most of the studies were no longer enrolling patients, so in only 37 cases
did consent forms have to be amended.
Seventeen studies had potential long-term risks -- "cancer etc." -- that
might occur even after the intervention had stopped. UBC's re-review
committee decided that in only two studies did patients need to be asked to
sign a revised consent form.
In one study, which appears to have been an experimental cancer treatment,
patients had not been told the drug might cause "some forms of cancer." In
another study, patients were not told an experimental drug had the
"potential to produce fertility problems."
Samarasekera's March 7, 2002, letter to McLellan generated a blizzard of
paper in Ottawa, as officials at Health Canada, the CIHR and NSERC tried to
decide what do about the "most serious" breach.
Officials at the research councils seemed dismayed at the approach taken by
UBC, which receives more than $300 million worth of research grants each
year, much of it from federal agencies and industry.
"You learned of the noncompliance issue in late August 2001. Why did you
not inform us until March 2002?" CIHR and NSERC officials asked in a letter
sent to UBC shortly after they learned of the problem.
They added: "Have you considered informing the subjects involved in the
trials? If not, why not?"
The federal documents also raise serious questions about UBC's re-review.
They show UBC was in such a hurry to try to fix things it continued to
break federal rules until Nov. 1, 2001, six months after the problem was
discovered.
This is because UBC failed to include two people "with broad relevant
research experience" on the ethics board that reviewed the projects, as
required by federal regulations.
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