FDA warns Hutch on clinical trial: Doctor cited for failures in areas of informed consent, patient safety

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Another clinical trial at Seattle's Fred Hutchinson Cancer Research Center has come under fire, this time from federal inspectors who say the doctors conducting the study "failed to provide basic elements of informed consent" to patients and to properly report deaths and other problems.

On the last day of 2001, the Food and Drug Administration sent a warning letter to Dr. Dana Matthews, listing seven violations of patient-safety regulations. Matthews, who has worked at The Hutch for 15 years, was the principal researcher in an experimental treatment for leukemia.

Hutch officials, while downplaying the significance of the warning letter, said it is the first in the 25-year history of the center. Federal authorities and independent experts, meanwhile, said such warning letters indicate serious problems. One FDA official said the letter reflects "systemic problems with the way they approach clinical trials" at the Hutchinson Center.

Hutch officials would not say whether the experiment is ongoing or has ended. In it, Matthews and other researchers used substances called monoclonal antibodies to deliver high doses of radiation through the blood to cancer patients.

The center, Matthews and five other Hutch doctors held a patent to the method tested in the federally funded experiment, but a spokeswoman yesterday said they had abandoned the patent.

Dr. Janet Eary, director of the University of Washington's Division of Nuclear Medicine, worked with Matthews on the study and also received an FDA warning letter listing three violations.

In the warning letter to Matthews, the FDA said:

• An unspecified number of deaths and other serious "adverse events" that may have been caused by the experiment had occurred but were not properly reported. The setbacks had been noted in annual reports to the FDA but not at the time they occurred, as the agency requires for safety purposes.

• Researchers misinformed some patients about how much radiation they would receive and failed to provide "an accurate assessment of foreseeable risks." Patients were asked to sign a consent form describing a certain range of radiation, while in fact there was no upper limit and some were given higher dosages.

• There was no evidence doctors had reviewed radiological scans crucial to determining whether the treatment would work on individual patients. Nor, in some cases, was there evidence doctors had approved radiation levels, or checked the doses to vital organs afterward.

• The FDA found "numerous examples of markovers and obscuring of original data" in records maintained by Matthews.

'Some systemic problems'

Neither Matthews nor Eary responded to requests for interviews by The Seattle Times.

Hutchinson Center officials would not respond to questions, except to offer a short written statement from Dr. Fred Appelbaum, who as the center's clinical director oversees the experiment.

In the statement, Appelbaum said the FDA's concerns were "essentially limited to issues of documentation" and that the medical center was still working with the FDA "so as to be in full compliance." He said also that the results of the experiment in question "are encouraging, resulting in some of the highest cure rates for acute myeloid leukemia ever reported."

Dr. Patricia Keegan, the FDA's deputy director for clinical trials in the Center for Biologics Evaluation and Research, said Appelbaum's response was an oversimplification and ignored legitimate safety concerns.

"I think that there are some systemic problems with the way they approach clinical trials," Keegan said. "To put it in the realm of documentation is to minimize that the documentation was not appropriate to safeguard the patient, which is why we took the serious action that we did."

The FDA issued the warning letter after three inspections and an exchange of correspondence. FDA spokeswoman Susan Cruzan said warning letters are "significant enforcement actions" that can lead to termination of a study, disqualification of researchers or a court injunction.

Warnings are rare, serious

Outside experts agreed that FDA warning letters are significant. Nationwide, 20 such warning letters were issued by the Center for Biologics last year, including the two on the Hutch experiment.

Among major medical-research institutions, such warning letters are even more rare. Officials at Memorial Sloan-Kettering Cancer say they have never received one. Johns Hopkins University received one in 2000 for continuing allergy studies after the FDA had ordered them put on hold, and M.D. Anderson Cancer Center in Houston got one in 1996 for misbilling patients.

Locally, Immunex Corp. of Seattle received one in 1999 for issuing a misleading press release on a drug in development, and Virginia Mason Medical Center was warned that same year about flaws in its research-review process, since corrected.

In his written statement to The Times, The Hutch's Appelbaum suggested that the warning was largely the result of confusion over paperwork:

"The concerns of the Food and Drug Administration were essentially limited to issues of documentation. Studies of investigational new drugs overseen by the (FDA) have unique requirements for the development of case report forms, documentation and reporting that differ from most other clinical research. Further, the (FDA's) monitoring policies are evolving. Our institutions are working closely with the (FDA) to modify aspects of our system of documentation so as to be in full compliance with their requirements."

The FDA's Keegan countered that the agency's requirements are long-standing and well-known, and the FDA relies on documentation to do its job of protecting patients and advancing research.

Dr. Thomas Puglisi, former director of compliance for the federal Office for Protection from Research Risks, said an FDA warning letter is "a serious matter."

"FDA does not issue warning letters unless it identifies serious problems requiring prompt corrective action," he said.

Three reports preceded letters

The FDA warning letters to Eary Dec. 4 and to Matthews Dec. 31 followed three separate inspection reports from June to October of last year. Matthews and Eary submitted replies to the FDA, but officials felt their concerns had not been adequately addressed. The Hutch refused to make those replies available. The Times has asked the FDA for them through the Freedom of Information Act; that request is still pending.

Hutch officials also declined to answer questions about whether the experiment is still active, whether the patient-consent forms have been changed, how many people may have been affected, and whether there was private funding for the trial. The Hutch has declined to release copies of the experiment protocol or the consent letter.

Susan Edmonds, media-relations manager, said Hutchinson Center officials may comment on the situation next week after sending another letter to the FDA.

The inspectors' findings were emerging last summer even as a specially appointed advisory committee to The Hutch was reporting that the center was in line with all federal regulations on human research.

Advisory panel was meeting

The advisory committee was formed last spring after The Times published reports on problems with two major clinical trials at The Hutch during the 1980s and 1990s.

Last March, the newspaper detailed that patients had died prematurely in experiments, that doctors had failed to properly inform patients of risks and alternatives, and that doctor-researchers had potential financial interests in drugs being tested. Both of those earlier experiments failed and are now the subject of lawsuits by patients' families.

The Hutch responded with sweeping denials but appointed the committee — headed by the Rev. William Sullivan, former president of Seattle University and a member of the center's Board of Trustees — to examine its current practices.

The Committee for Patient Protection in Research Trials, as it was called, recommended that the center's board adopt what would be the nation's toughest ban on financial conflicts. At the same time, though, the panel assured the public and the trustees that the center was fully in compliance with regulations.

The committee's report, issued Sept. 7, made no mention of the FDA's adverse findings — the first dated June 15.

The June inspection report said Matthews' experiments in radioactive antibodies were lacking proper safety, monitoring, quality assurance and reporting procedures. For instance, it said, seven of 27 people were hospitalized from unfavorable or unintended symptoms that may have been caused by the experimental drugs, but these weren't reported to the FDA or to The Hutch's internal-review board, as required.

Sullivan says he had heard about violations listed in the first inspection report during a meeting of the Board of Trustees executive committee in late June but didn't discuss it with the advisory panel, which met through August.

"Our view," Sullivan wrote in an e-mail Thursday, "is that such a list is not a final agency judgment about non-compliance. This final judgment from the agency occurred upon receipt of the 'Warning Letters.' "

FDA guidelines say its investigators write reports "when deviations from regulations are observed." If the problems aren't corrected, the investigators' superiors follow up with warning letters.

Reviewer wasn't told

Dr. Ernest Prentice of the University of Nebraska Medical Center, who was hired by the advisory panel to check The Hutch's practices, said he had not been made aware of the FDA reports.

The University of Nebraska Medical Center itself has never received an FDA warning letter, Prentice said. Warning letters, he said, are "significant, and the institution has to correct them promptly."

Helen McGough, manager of the Human Subjects Division at the University of Washington, speaking generally, said it's not unusual for FDA inspections to result in findings of violations. "So usually you fix them and you fix them quick, and that's the end of it. A warning letter is much more serious. It means it's gone beyond the (inspection report), that they counseled you, and you didn't fix it."

McGough said that in her 13 years, the FDA has not issued any warning letters on UW-sponsored research. McGough said she knew about the warning letter to Eary and phoned her to make sure she was working with the Hutchinson Center on it.

A leader in leukemia research

The Hutch is a prime location for testing new treatments on leukemia patients, who come here from all over the world. It performs more stem-cell and bone-marrow transplants than any other medical center.

Matthews, 46, is a 1981 graduate of the University of Washington School of Medicine with a specialty in pediatrics. She's been pursuing radioactive-antibody experiments most of her career.

Investigators at The Hutch began attaching radioactive iodine to antibodies in 1986. While some researchers focused on antibodies that zeroed in on tumor cells, Matthews and her mentor, Dr. Irwin Bernstein, worked with antibodies that attached to common white blood cells. They figured those could irradiate cancer in places such as the lymph nodes, spleen, marrow and blood, while sparing the liver, kidneys and lungs.

Medical journals and federal grant records show The Hutch has conducted at least five major experiments involving more than 100 cancer patients with variations of the treatment during the 1990s, as well as mouse and monkey experiments.

Matthews and Bernstein applied for a patent on the new method in March 1990. Other inventors listed on the patent were Drs. John Hansen, Paul Martin, Claudio Anasetti and Appelbaum. The 20-year patent was issued in December 1993 and assigned to the Hutchinson Center. It was unclear when or why the patent was abandoned.

Eary, 47, of the UW, did not share in the patent.

Data reported by Matthews indicate the treatment tested may be effective: She wrote recently that 16 of 19 patients with acute myeloid leukemia in first remission were surviving disease-free an average of about two years, and 10 of 34 patients with more advanced cancers were surviving disease-free an average of about four years.

Times staff reporter David Heath contributed to this report.

Duff Wilson can be reached at 206-464-2288 or dwilson@seattletimes.com.