During Protocol 126, The Hutch adopted a rule barring scientists from work in which they have financial stake.
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Copyright © 2001 The Seattle Times Company
Changes raise more concerns
Hansen began spending more and more time at Genetic Systems. He gave Martin, a postdoctoral student in his early 30s who had spent two years in the lab refining the antibodies, the title of principal investigator in Protocol 126.
This would be Martin's first experiment involving humans.
The initial results proved next to nothing. About half of the first group of subjects got GVHD - exactly as would be expected without T-cell treatment.
The antibodies alone hadn't killed T-cells in people as they had in mice. Then the researchers asked the review committee to approve major changes in the experiment. They wanted to add enzymes known to make the antibodies more lethal to T-cells. And they wanted more and healthier patients as subjects, people strong enough to survive years after a transplant so they could monitor the long-term results.
When the experiment went back to the Human Subjects Review Committee in April 1983, one member, Dr. Robert Bruce, a UW cardiologist, raised an alarm: One of the antibodies in the new proposal had been associated in another study with the emergence of unexpected new cancers.
Bruce recommended continuing Protocol 126 if and only if Martin established rigorous criteria to stop the experiment immediately if such problems occurred.
"The informed consent should at the very least indicate that some unexpected adverse effects have occurred," Bruce wrote. "The risk of fatality from an additional malignant process ... can hardly be overlooked in the statement of potential risk."
But the consent form wasn't changed. And there is no evidence the new review panel was ever told about the broader objections raised by its predecessor. The concerns Kennedy had raised about the role of T-cells in grafting and relapse were not addressed.
On May 26, 1983, the next stage of Protocol 126 was given a green light. The research doctors started looking for new patients to enroll.
Later that year, The Hutch's Board of Directors adopted a conflict-of-interest policy. It said scientists "shall not participate in any (research) involving the Center in which the member has an economic interest," including any form of ownership or any outside pay.
Hansen and Martin say they were never told about the policy. And even if they had known, they insist, their work at The Hutch had no bearing on business prospects at Genetic Systems.
The company was developing products to diagnose disease, they say, not to treat it. Given that, they say, the T-cell experiment could not possibly have benefited Genetic Systems or their stock.
Yet the company's own filings with the Securities and Exchange Commission from that period show plans to use antibodies to treat cancer. And Nowinski told The New York Times in 1983 that he expected to move from diagnosis to treatment.
The doctors' business partner, Blech - who was later convicted of securities fraud in an unrelated case - said in a recent interview that the big money was in treatment, and that was where Genetic Systems had planned to go.
Martin and Hansen insist Genetic Systems was not involved in Protocol 126. But Hansen was a full-time employee and director of Genetic Systems at the height of the trial. He is listed as a co-author of the study every step of the way; he participated in major decisions and tracked results.
Martin was working for a Genetic Systems official intimately involved with the conduct, results and funding of the experiment.
Further, the doctors' agreements with Genetic Systems obliged them to give the company the fruits of their research on company products, even if the company did not formally sponsor the research.
New panel raises questions
In September 1983, The Hutch signed up a new group of volunteers for the Human Subjects Review Committee, combining it with a similar group at Seattle's Swedish Medical Center, where Hutch doctors treated patients.
The committee was given a new title: the Institutional Review Board, or IRB.
Dr. Henry Kaplan of Swedish Medical Center, featured here on a Seattle Magazine cover, saw problems as soon as he was appointed chairman of an experiment-oversight board in 1983. |
Dr. Henry Kaplan of Swedish, who would become one of the Northwest's leading oncologists, was appointed chairman. Dr. John Pesando of The Hutch was recruited to be a member. Pesando was reluctant because of the demands of his own research but agreed, hoping the volunteer work would help his chances of promotion.
Pesando says he and Kaplan "walked in and found problems everywhere we looked."
"These included unsafe ongoing protocols," Pesando said. "So we had double jeopardy of not only putting the brakes to new research, but trying to stop things that had already been approved."
The experiments that raised their eyebrows, and their concerns, the highest were the tests of new monoclonal antibodies.
Kaplan complained that antibodies were being used in "a completely uncontrolled fashion," and that animal testing had been insufficient. He wasn't told that similar objections had already been raised and ignored.
In one of his first acts as chairman, Kaplan wrote to Thomas asking about rumors that researchers had financial interests in a company that would use the findings from Protocol 126.
"What checks and balances are utilized to deal with potential conflicts of interest between academic and financial considerations of the staff?" he asked.
Thomas replied with a strongly worded letter denying any financial conflicts of interest and refusing the IRB's request to review each antibody separately for human safety.
"I think Committee members have not only an obligation to review the ethical aspects of this work, but also an obligation to assist us and not impede our research, which is directed toward solving some of those problems that are killing the children and young adults who come to us with fatal disease," he wrote.
In fact, the IRB had no such duty to assist research. Federal law gave the panel a single, pointed mission: "Protect the rights of the human subjects."
Nevertheless, Kaplan said he got a clear message from the future Nobel Prize winner who ran The Hutch. "It certainly didn't appear that we had the power to investigate anything once I got that letter from Thomas."
But what Thomas wrote was mild compared with some of what Pesando heard in the hallways. Thomas and others were enraged with the challenge to their research, Pesando said.
"Dr. Thomas had a fearsome reputation," Pesando said. "You crossed him at your peril."
'Who the hell are YOU?'
IRB members felt unable to do a proper scientific assessment of Protocol 126. They felt they didn't have the information or the power to do their job.
Six weeks after Thomas' letter, Kaplan, on behalf of the IRB, asked Hutch President Dr. Robert Day to set up a new, independent body to consider the merits of all the monoclonal antibodies under study. The IRB termed them "entirely new, experimental drugs" which had not met normal safeguards.
Day |
"We saw this coming, that we would eventually be unable to resist the people who controlled our lives, careers and salaries," Pesando said. "That's why we wanted an outside review."
Day refused to set up an outside panel, saying it would cost too much and reveal secrets to The Hutch's competitors.
Kaplan also contacted the National Institutes of Health for advice on how the panel could act, but got no help.
In January 1984, IRB members heard that two patients in the newest version of Protocol 126 had failed to engraft transplanted marrow. Normally, properly matched marrow was accepted 99 percent of the time, so these rejections were alarming.
They meant patients might actually die from their treatment before they would even reach the point where GVHD was a possibility.
Pesando started warning patients to stay out of the protocol. Some did; some did not.
Day summoned the senior clinical staff to a meeting with Kaplan and Pesando. Day would not curb the protocol or start an outside review. But he agreed to one demand: The lowest-risk patients, who had the most to lose from graft failures, would not be allowed to enroll in Protocol 126.
"We got something - granted, not very much, because we had no power - but we got the best patients out," Pesando says.
The research team did not appreciate those efforts. Pesando says Thomas asked him at a scientific staff meeting, "Who the hell are YOU to question what we do around here?"
Graft failures, relapses high
Death by leukemia occurs as cancer cells crowd out normal cells in the blood. Victims suffer infections, bleeding and oxygen deprivation.
Death by graft failure after a bone-marrow transplant is an accelerated but no less agonizing process. The victims, weak from Hiroshima-dose radiation and chemotherapy, fail to accept the marrow that could save their lives. They suffer all the effects of a destroyed immune system and die of infections and bleeding.
Graft failure is extraordinarily rare in normal cancer work, occurring 1 percent of the time in tissue-matched transplants between siblings.
But of the 20 people enrolled in Protocol 126 between June 1983 and March 1984, at least seven of them died from graft failure.
At least five patients suffered relapses of their cancers, which was also an unusually high rate, believed to be caused by the absence of T-cells to fight off stray cancer cells.
The dead included people who stood a good chance of being cured with standard therapy. Among them:
• Ruth Agnes Fisher, a Los Gatos, Calif., computer programmer. She was 38 years old when she learned she had leukemia.
It was a relatively mild form that could be bothersome but not fatal for many years. She also had a perfectly matched sibling donor for a bone-marrow transplant. With the standard treatment, she had a 60 percent likelihood of being cured.
But Fisher was enrolled in Protocol 126. Her bone-marrow transplant failed to engraft and she died of cardiac arrest on Jan. 27, 1984.
"The whole thing was sort of a blur," her widower, Joe Fisher, says today. "T-cells - I thought that's what makes the transplant work."
• Jacqueline Couch, 31, an attorney for the city of New York who lived in Summit, N.J. She, too, came to Seattle for a transplant with a relatively good prognosis. She, too, was signed up for Protocol 126.
She, too, died of graft failure almost certainly caused by the experiment.
Her brother, Richard Stanford Jr. of Yardley, Pa., who donated his marrow, says today, "For some reason - we were told the doctors didn't know why - it all of a sudden stopped producing cells."
No one ever told the family what went wrong. "It took me a long time to get over that," Stanford says.
• Lourdes Caridad Llera, 32, a homemaker from Tampa, Fla. She died in May 1984 after graft failure.
• Carolyn Sue Obermeyer, 37, a homemaker from Oldenburg, Ind. She died in September 1984 after graft failure.
• Lawrence Haspel, 48, a New York orthodontist. He died after graft failure and a second transplant attempt.
• Bina Bidasaria, 31, a homemaker from India. Ten months after a transplant with a brother's matched marrow failed to engraft, she tried a second, then died in Seattle a month later. Her widower, Mahavir Bidasaria, says he doesn't remember talking about T-cells and wasn't told why she had graft failure. "All those terms were not very familiar to us."
• Paul Mahler, 41, chairman of the anthropology department at Queens College of the City University of New York. He suffered graft failure, tried a second transplant after the first one failed and died in Seattle seven weeks after that.
The Seattle Times identified these people through death certificates and public records.
Fisher and Couch had been Pesando's patients for a time when he worked on the transplantation ward. Their deaths affected him deeply. He believed they could have survived a standard bone-marrow transplant.
In retrospect, Martin concedes the results of the experiment on chronic leukemias at that point were "awful."
"A lot of rejection, a lot of recurrent malignancy," he said in an interview. "And so it didn't work. It was a bad idea."
'Something's really fishy here'
The Hutch didn't have to report these patient deaths to the federal government. Experimental drugs that do not cross state lines are not regulated by the Food and Drug Administration.
The Hutch didn't alert the King County Medical Examiner, either, despite state and county requirements to report unexpected deaths associated with medical procedures.
Martin was required by federal and Hutchinson rules to report the deaths to the IRB, but he did not.
Inside the corridors of The Hutch and Swedish, however, word of the unusual deaths spread. And the drumbeat against Protocol 126 intensified.
Dr. Rainer Storb - the Hutch co-founder who had opposed the experiment from the start - says he spoke out in staff meetings time and again over the years.
"It was becoming evident on the wards that, you know, something's really fishy here," Storb recalls. "You have to have a very keen eye and bring the whole thing to a screeching halt if something goes wrong."
Storb had long been The Hutch's top expert on GVHD. In the same hallways and at the same time that patients were dying in Protocol 126, Storb was perfecting a better treatment against GVHD.
He had found that a combination of two FDA-approved drugs, methotrexate and cyclosporine, prevented GVHD and treated its effects.
Storb had started enrolling patients in his own clinical trial in August 1983, just as the most dangerous arm of Protocol 126 began.
He published his work in the New England Journal of Medicine. He had cut rates of acute GVHD from 54 percent to 33 percent and had raised the 18-month survival rate from 55 percent to 80 percent. He had had no problems with graft failures or relapse in 93 patients.
Storb came closest to a public attack on Protocol 126 when he cited it twice in passing in his New England Journal article, noting "survival rates that were poorer than those seen among patients who received untreated marrow."
Storb's regimen has stood the test of time. It remains the gold standard for treatment of GVHD to this day.
There is no evidence any Protocol 126 patient was ever told about the Storb treatment, even though its positive results had emerged. Instead, they were told there was no alternative to Protocol 126 to prevent GVHD.
It was a careful choice of words. Thomas' wife, Dottie, a program aide who helped with Protocol 126, argued in a memo that the Storb method was "treating" GVHD but only Protocol 126 was "preventing" it.
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Dr. Robert Bruce comments on Protocol 126, April 13, 1983 (424K PDF)
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Fred Hutchinson Center Conflict-of-Interest Policy, June 9, 1983 (336K PDF)
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Dr. Henry Kaplan's first letter to Dr. Thomas questioning safety of antibodies and conflicts of interest, Sept. 28, 1983 (660K PDF)
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Dr. Thomas' reply denying conflicts and warning IRB not to impede research, Oct. 14, 1983 (2MB PDF)
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Dr. Kaplan's letter to Dr. Robert Day asking for independent scientific review, Nov. 30, 1983 (416K PDF)
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Dr. Day's reply refusing an independent review but removing healthiest patients, Feb. 23, 1984 (540K PDF)
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Dottie Thomas' letter to board argues there is no alternative treatment, May 1, 1981 (244K PDF)
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