Disputed clinical trial is 'on hold,' Hutch says

E-mail this article Print this article

The Fred Hutchinson Cancer Research Center has suspended a clinical trial authorities say violated federal patient-safety regulations.

Dr. Lee Hartwell, president of the Hutchinson center, said he expects continuing reforms and an upcoming letter to satisfy the U.S. Food and Drug Administration (FDA) and allow the experiment to resume.

FDA officials had no comment yesterday.

The suspension affects one of the premier clinical trials of a leukemia treatment in recent years at the world's largest center for bone-marrow transplants. The National Cancer Institute has poured more than $11 million into a 13-year series of related experiments in Seattle attaching radioactive isotopes to blood cells in mice, monkeys and more than 100 leukemia patients.

Bone-marrow transplants are a standard treatment for many kinds of leukemia. The experiment was exploring ways to supplement standard full-body radiation therapy of patients.

Previously, Hutchinson center officials had declined to say whether the trial had been suspended, whether patients were affected or how the center was responding to FDA warning letters made public in The Seattle Times on Sunday.

Key FDA finding disputed

Tuesday, Hartwell e-mailed the center's doctors and staff, admitting some of the violations listed in a recent FDA notice, taking issue with others and disclosing the clinical trial is "currently on hold while we complete the development of enhanced procedures for documentation and monitoring."

A Hutch spokeswoman yesterday declined to say when the study was suspended or to answer questions. Drs. Dana Matthews and Janet Eary, the researchers who had received the FDA warning letters, didn't return phone calls and e-mails seeking comment.

Steven Masiello, director of the FDA Office of Compliance and Biologics Quality, wrote in a Dec. 31 letter to Matthews, the principal researcher, that the doctors had "failed to provide basic elements of informed consent" to patients or to properly report deaths and other problems.

According to FDA inspectors, the doctors had told patients there was a maximum radiation dose when in fact there was no upper limit, and some patients received more radiation, with more risk, than they'd agreed to.

Hartwell disputed that key finding. His e-mail said the people who enrolled in that arm of the experiment, known as Protocol 557, were never told there was an upper limit to the radiation but were told the radiation would be "e.g., 50-300 milliCurie."

Hartwell wrote that "the term 'e.g.' meant 'for example.' This indicates that the milliCurie levels that were mentioned were only examples, and were not the limits on the radiation doses to be administered."

He added, "We are reviewing current consent forms to be sure they are clear as to whether there are limits of radiation."

Hartwell also disputed the FDA finding that "serious adverse events," such as deaths and injuries, were not reported to the agency as quickly as required. He said that the Hutch only needed to expedite reporting of unexpected events and that some serious adverse events such as deaths in this experiment were "expected."

Indeed, FDA regulations confirm that only unexpected deaths and injuries need to be reported within seven days, but the FDA warning letter said the events at the Hutch had met this criteria. The FDA said several patients' setbacks should have been reported faster so the FDA could monitor safety in the trial and that Matthews had agreed that adverse events had not been reported appropriately to the FDA.

Hartwell wrote: "The FDA has asked us to do a better job of defining unexpected events in our protocols. We have revised our protocols to do so."

The FDA letter also repeatedly said Hutch doctors had failed to provide any evidence that they had actually done what they promised to do in key parts of the experiment.

Hartwell wrote that this was a paperwork error. "The doctors involved did review all radiological scans, approved all radiation levels, and checked the doses to the vital organs of all patients," he wrote. "The doctors failed to document some of these reviews in the research record, and we have instituted procedures to avoid this problem in the future."

Finally Hartwell noted that the FDA had found violations in the Hutch's "method of correcting data in the research record," including unsigned markovers, the use of correction fluid and obscuring of original data, "and we have changed our methodology to be in compliance with their standards."

Reply to FDA 'in a few days'

Hartwell is a 2001 Nobel laureate, largely for work in yeast genetics at the University of Washington since 1968. He was named Hutchinson president and director in 1997.

FDA officials yesterday declined to talk about Hartwell's e-mail.

Dr. Patricia Keegan, FDA deputy director for clinical trials in the Center for Biologics Evaluation, last week said that the FDA review showed "systemic problems with the way they approach clinical trials" at the Hutchinson center and that a response blaming documentation was "minimizing" serious issues. Two previous letters from the Hutch to the FDA had failed to satisfy the agency.

Hartwell said the center would send another formal reply to the FDA "within a few days" and he was confident this would satisfy concerns.

He said any changes to the protocols would be submitted to the center's internal-review board for approval, "after which the clinical trials should be able to resume."

The Hutchinson studies use radioactive iodine attached to white-blood-cell-seeking antibodies to deliver extremely high doses of radiation through the blood to leukemia patients. One study found about 90 percent of patients would get more radiation that way in their spleen, lymph nodes and bone marrow than in their liver, lungs and kidneys, making it an attractive supplement to the standard full-body attack on leukemia.

The radioactive-antibody procedure is followed by chemotherapy, total body radiation and a bone-marrow transplant.

The Hutchinson work under FDA review began in 1988 and evolved through a series of overlapping protocols or discrete experiments testing escalating doses and different types of leukemia, transplants and patients. It was unclear yesterday which of these protocols, perhaps five, had been suspended, but the FDA and Hartwell referred to plural protocols.

Hutch Drs. Matthews, Fred Appelbaum, Irwin Bernstein, John Hansen, Claudio Anasetti and Paul Martin applied for a patent in 1990 to this new method of radiation delivery, hoping it could lead to marketable products. But the federal patent office said the patent had been abandoned Feb. 6 due to nonpayment of maintenance fees.