Death prompts scrutiny of research risks
By Sara Shipley
When John and Oksana Rogers learned that their year-old daughter, Daniella, had cancer, they knew she might die.
But they hardly expected that the medicine that was supposed to save her would instead take her life.
"It wasn't the cancer that killed her. It was the treatment," Oksana Rogers said.
The chemotherapy drugs Daniella received at St. Louis Children's Hospital as part of a clinical trial caused the blood in the small vessels of her liver to clot like curdled milk. Three other children died of the same side effect before the study's sponsor, Children's Oncology Group of Arcadia, Calif., and the National Cancer Institute temporarily suspended the trial last year.
Now a federal public health agency has ruled that Washington University Medical School, a local participant in the trial, should have done a better job of warning patients about complications from the potentially fatal liver disease.
The Office of Human Research Protection, an arm of the U.S. Health and Human Services Department, determined last month that the medical school should have spelled out the risk of veno-occlusive disease of the liver, a rare but well-known reaction to commonly used cancer-fighting drugs. The disease occurred in about 1 out of 20 patients in the trial. Four of the 360 children enrolled died of it.
The agency's finding carries no sanctions or fines. Washington University now warns remaining participants in the cancer trial specifically about the disease.
Washington University wouldn't allow the Post-Dispatch to interview its doctors about Daniella's case because the Rogers family has threatened to sue. However, the university released several statements and documents that defend its actions.
"Washington University School of Medicine takes extremely seriously its commitment to add to medical knowledge through clinical trials that are always conducted with patients' safety and best interests as the highest priority," the school said in a written statement. "We express our sincere regret and heartfelt sympathy to the Rogers family for their tragic loss."
Daniella's case is one of the latest to raise questions about the massive clinical research industry, and to provoke debate about how far researchers must go to make sure subjects understand the risks.
The number of clinical trials has increased tenfold in the past 25 years, according to the federal Food and Drug Administration. The National Institutes of Health provided $7.2 billion in public funding last year for clinical research, a figure expected to rise 11 percent this year. Major private pharmaceutical companies spent $30 billion last year on research and development, with at least 20 percent of that amount spent on human research, industry figures show.
Dr. David Lepay, head of the FDA's Office of Good Clinical Practices, said his agency's inspectors find far fewer problems now than they did 25 years ago, when perhaps 20 percent of trials failed to meet key regulations. Now, the number of violators is around 2 percent, he said.
But as the field grows, and scrutiny increases, serious problems have surfaced:
In 2001, Johns Hopkins University temporarily lost its government funding after admitting it was responsible for the death of a healthy volunteer in an asthma experiment.
In 1999, the FDA shut down a gene therapy experiment at the University of Pennsylvania after an 18-year-old subject died. The agency charged that investigators violated federal regulations and failed to adequately protect the lives of patients.
Washington University's School of Medicine, which ranks fourth in federal research funding nationwide, has never been charged by federal agencies with such a serious violation. The medical school received more than $302 million in NIH funding in fiscal year 2002, following behind Johns Hopkins, the University of Pennsylvania, and the University of California at San Francisco, spokeswoman Joni Westerhouse said.
Westerhouse said the medical school is involved in about 3,000 clinical trials, and it receives only two to three complaints per year from patients. Calls go to the Human Studies Committee, which is charged with ensuring that the research is safe and ethical.
Officials at the Washington University medical school say they informed the Rogers family about the risks inherent in chemotherapy, which uses highly toxic chemicals that kill healthy cells along with cancer cells.
Westerhouse also provided a letter dated Sept. 3, 2002, from the FDA stating that the agency found "no significant deviations" from federal regulations in its investigation of Daniella's case. Both the FDA and the Office of Human Research Protection conducted investigations because of complaints filed by the Rogers family.
John Rogers said he felt vindicated by the finding of the Office of Human Research Protection that the university failed to fully inform trial participants about the risks of veno-occlusive disease. "It makes us feel a little bit better that the government acknowledged they (Washington University) didn't do the right thing," he said. "But it doesn't bring Daniella back."
"The best treatment option"
Since their daughter died last spring, John and Oksana Rogers have become activists. They set up a Web site, www.daniellarogers.org, which documents their allegations. The family says that Daniella might have lived had Washington University properly informed the couple of the risks and monitored more closely for symptoms of the disease. The university denies responsibility for the girl's death.
Daniella's memory fills the family home in Florissant. On a recent visit, framed photos showed the little girl, bald from chemotherapy, smiling and wearing a parade of hats. A small Christmas tree held her ornaments. Her bedroom, much the way she left it, contained a shrine where Oksana's mother, a Russian immigrant, prays every morning.
The Rogers family first noticed a lump in Daniella's shoulder in the fall of 2001, during a visit to see Oksana's family in Russia. When the family returned from the trip, doctors at Washington University took a biopsy of the mass and pronounced it to be nonmalignant, John Rogers said. When the lump continued to grow, doctors removed it last February. That's when the family was told that it was a malignant form of cancer.
Daniella had rhabdomyosarcoma, a tumor of the skeletal muscles that makes up about 7 percent of childhood cancer cases. Doctors told the family that, with treatment, Daniella had about a 70 percent chance of survival. Her parents were hopeful.
John Rogers wanted the best care for the couple's first and only child. He was familiar with clinical research because of his work at the Barnes Retina Institute as a medical photographer.
When Dr. David Wilson said they could join a cancer trial, the Rogers family jumped at the chance. John Rogers said he assumed Daniella would get the most attention that way.
"We had just found out our daughter had cancer. Most parents are desperate at that point, and willing to do anything, and being presented with this being the best treatment option, we're like, 'Yeah, let's do it,'" John Rogers said.
The family did seek a second opinion from another area doctor. After being reassured that Daniella's treatment would be the best available, the family signed up.
John and Oksana Rogers signed a document that explains what the patient and her guardians need to know about the research. Called an informed consent document, it is required by federal law to disclose risks and inform patients of their rights.
Most of the nine-page document contains legal disclaimers, signature pages and schedule information. About two and a half pages are devoted to charts explaining the "risks and discomforts that may be associated with this research." Possible side effects for radiation and six drugs used in the study are listed briefly, including one line that says simply: "liver damage."
In the control group
On Feb. 28, 2002, Daniella began therapy in a nationwide study comparing the standard chemotherapy treatment for rhabdomyosarcoma with a newer drug combination.
She was in the control group, which received the regular treatment - a combination of the drugs vincristine, actinomycin-D and cyclophosphamide, or VAC, dubbed by Washington University as the "gold standard" for decades.
Subjects in the experimental group received VAC alternating with another group of drugs. In a previous study, published in 1997, an estimated 3.1 percent of patients receiving the VAC regimen developed liver disease, but no one had died of it.
The family and Washington University agree about these basic facts of what happened in the two-month course of treatment:
Daniella responded normally to the drugs until the week of April 24. On that Tuesday, her chest catheter bled abnormally. On Wednesday, she got a transfusion of platelets and red blood cells. On Thursday, she got more platelets and another dose of chemotherapy medicine.
Early Friday morning, Daniella threw up blood. Upon arrival at Children's Hospital emergency room, doctors found her listless with a distended abdomen.
Tests confirmed that Daniella had veno-occlusive disease. There is no cure, although patients sometimes recover. Despite aggressive care, Daniella's liver and kidneys shut down, her brain swelled, her breathing slowed and her heart faltered. Daniella, then 20 months old, died a week after admission, on May 3.
Other deaths reported
John Rogers said he never even heard of veno-occlusive disease before his daughter was diagnosed with it. He was outraged when he found out that two other children in the same study had already died of it before Daniella became ill.
According to Washington University, its doctors didn't know anyone had died either. The national sponsor of the study, Children's Oncology Group, had detected 15 cases, including two deaths, from the liver disease as of last February. After an internal review, the group posted the report to its Web site two months later, on April 23 - just a day before Daniella's steep decline began.
Children's Oncology Group recommended continuing the study as planned while closely monitoring the incidence of the liver disease, according to Washington University.
The university said Daniella's doctor hadn't seen the Web site before she got sick. But even if he had, it wouldn't have changed the outcome, the university said.
The medical school's doctors were well-informed about the disease, monitored for it, made a timely diagnosis of symptoms and began supportive care within a reasonable amount of time, Washington University said.
"Although tragic, the patient's death did not result from any lack of awareness or vigilance" on the part of the medical school, according to a letter dated Aug. 1, 2002, from Dr. Philip Ludbrook, chairman of the Washington University Medical Center Human Studies Committee, to the Office of Human Research Protection.
Within a few months of Daniella's death, another patient in the trial died of veno-occlusive disease. Children's Oncology Group and the National Cancer Institute suspended the study in August.
Washington University argues that the drugs Daniella received were the same she would have gotten anywhere, whether in a study or not.
But John Rogers believes that the dose she received was much higher than it should have been. According to his calculations, based on the manufacturer's package insert, she got up to twice as much as she should have, and over a shorter time period.
Dr. Gregory Reaman, chairman of Children's Oncology Group, said in an interview that the dosage outlined in the original protocol was only "modestly" higher than that used in past studies and "well within the standards we've used for many years." He also said the drugs were given in one day, rather than over a five-day period, to make it more convenient for patients.
When the trial later resumed, the dosage was decreased, especially for younger children, to address the liver toxicity problem, Reaman said.
Another change: The risk and symptoms of veno-occlusive disease were added to the model informed consent document. Washington University expanded its own consent form in May, at the Rogers family's request, and adopted the more extensive model wording in July.
"Needs to be crystal clear"
Why didn't Washington University spell out the risks earlier? According to Washington University's letter, it was because the university didn't want to confuse parents with medical jargon.
The university strives to use simple, understandable wording in its informed consent documents, according to Ludbrook's letter. He cited a national committee that recommends that "documents be written at an eighth-grade or lower reading level."
To John Rogers, that's unacceptable. "If you have to put everything in eighth-grade terminology, that leaves out a lot, and that's wrong," he said.
Dr. Arthur Caplan, a nationally recognized medical ethicist at the University of Pennsylvania, said informed consent documents should be simple to read. But that doesn't mean they should omit details that parents would want to know, he said.
Whether the risk of death is one in a hundred or one in a thousand, the patient has the right to be informed, he said. "It has to be very specifically spelled out, and it needs to be crystal clear," Caplan said. "In a sense, you can't overinform."
Caplan added that parents of sick children often suffer from what he calls "therapeutic misconception" - they only want to hear good news, and they don't really absorb bad news. They see a clinical trial as personal therapy, when really it's just an experiment.
"I think it's harder to accept deaths from treatment than from a disease," he said. "Disease is an act of God, while treatment can be controlled."
Ronald Munson, a bioethicist at the University of Missouri at St. Louis who also serves on Washington University's Human Studies Committee, said it's normal for the parents of a child who died to question everything, even well-intentioned doctors.
Should the university have explained the risk of this specific disease?
Should the sponsor have informed Washington University of the other deaths sooner?
Even if the parents knew the risk, would they have chosen to go forward? There are few other treatment options available, and they all carry risks.
"I think it's important to keep in mind all these matters. Yes, there's a risk of using the drug, but there may be a bigger risk in not using it," he said.
John Rogers said he accepts the risks of research; he just believes parents should know exactly what they're getting into.
"(Researchers) need to tell parents there are other options, and tell the parents the side effects and the risks of treatment," he said.