Patients never knew the full dangers of clinical trials on which they staked their lives
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AT A KITCHEN TABLE in a noisy apartment in the Flatbush neighborhood of Brooklyn, N.Y.:
David Blech, a 24-year-old songwriter and entrepreneur, sits with his brother and father. Like expectant parents choosing a baby name, they bark ideas for what to call their just-invented company: "DNA Techniques." "Hybridoma Service Center." "Genetic Systems."
"That's it!" Blech calls out, rising excitedly. "Genetic Systems Company!"
The Blechs will start with that name. They will use it, shares of stock and personal charm to recruit top cancer doctors to jobs and board positions. And, they dream, they will all get rich in the nascent biotechnology boom of the 1980s.
AT A KITCHEN TABLE in a quiet house in rural Heflin, Ala., five years later:
Becky Wright, a 36-year-old housewife and mother of three, sits with her husband, Pete, owner of the local drugstore. Their talk is not about dreams, but a nightmare: Becky has leukemia.
Pete has searched for the best place in the world to take his wife for treatment. His choice: the Fred Hutchinson Cancer Research Center in faraway Seattle.
They are hopeful. "The Hutch" is the pioneering institution in transplanting bone marrow - by then a proven treatment for the type of leukemia Becky Wright has - and she is the perfect candidate, with a donor sister whose marrow matches hers.
Doctors tell the Wrights that with a standard transplant, chances are good that Becky will live to see her youngest, a 5-year-old girl, grow up.
But when the couple travels to Seattle in 1985, Becky is not given a standard transplant.
Instead, she is thrust, unwittingly, into a world where the quest for cure gets tangled in the pursuit of fame and fortune. The world of David Blech.
At the urging of her Hutchinson Center doctors, Becky Wright joins an experiment in which eight manmade proteins are added to her sister's bone marrow before it is transplanted.
Some of those proteins belong to a Seattle biotech company - a company named Genetic Systems.
Some of Wright's doctors at The Hutch were among David Blech's recruits. The doctors - and The Hutch itself - were invested in the company Blech and his family had invented in their Flatbush flat.
By the time Wright was enrolled in the clinical trial, the doctors knew it wasn't working. Transplants were being rejected at alarming rates. New cancers were appearing and old ones reappearing far more than they normally would.
All were problems directly attributable to the experimental treatment.
The doctors didn't tell the Wrights any of that.
Not about the 11 patients who had already died. Not about other, less-dangerous ways of treating her disease.
Not about their own financial interests.
Becky Wright died of causes directly attributable to this experiment, as did at least 19 other people, according to evidence in medical journals and Hutchinson Center documents.
Odds are high that some of them would otherwise have survived a standard transplant and lived full lives. Many of the others likely would have lived at least a year or two longer than they did - a year or two they would have shared with their spouses, their children, their families and friends.
The story of Protocol 126, as this experiment was called, has never been told. Federal and state investigators looked into Protocol 126 for a while, then closed their investigations half-completed - leaving one investigator "saddened and alarmed" at the lack of follow-through.
During the 12-year span of the trial, several doctors at The Hutch tried to curb it. They said it was hurting rather than helping patients, and that mice or dogs rather than humans should be the test subjects. They complained that patients weren't being told about the risks, the alternatives, the researchers' financial conflicts.
As Dr. John Pesando, a member of a Hutch committee charged with protecting the rights of patients, wrote to federal officials in 1998:
"Many patients died at the Fred Hutchinson Cancer Research Center when the Institutional Review Board charged with protecting them was shamelessly used and abused by senior staff."
Hutch management "denied the existence of financial conflicts of interest, refused to halt the protocols, and refused to have protocols reviewed by independent outside examiners," Pesando wrote.
The researchers involved were Dr. E. Donnall Thomas, Hutch co-founder and clinical director and winner of the 1990 Nobel Prize in medicine; Dr. John A. Hansen, head of a tissue-typing lab and later clinical director; and Dr. Paul J. Martin, a young oncologist.
When the review board questioned the work of these doctors, Pesando said, board members were "lied to, intimidated, ignored and punished." Thomas argued in writing that it was the board's job to promote, not hinder, the research.
That's not what federal law says. By law, the board was to ensure that risks to patients in clinical trials were minimized in relation to potential benefits, and that patients fully understood those risks before consenting to participate.
More than 100 interviews and 10,000 pages of documents - including Becky Wright's consent form - reveal that neither occurred in Protocol 126.
Thomas refuses to discuss the trial or his financial holdings. The other doctors involved defend their actions, saying they were driven by science and that money issues didn't affect them.
Martin adds: "I don't think survival is the best measure of outcome in these studies."
Fifteen years after his late wife began her treatment at The Hutch, Pete Wright, who still runs the Wright Drug Co. in Heflin, was shocked to learn all he didn't know: That other Hutch doctors had tried to stop the experiment. That the doctors running the trial had financial interests in it. That there was an alternative treatment with a higher likelihood of success.
"To say it's disturbing is an understatement," Wright said.
"All these years I have told myself that she got the very best care possible and I swore that would be the case when she was diagnosed. It makes me want to buy a plane ticket to Seattle and beat the hell out of somebody."
The biotech boom begins
When young David Blech went recruiting for his fledgling company, he found a kindred soul in the upper-left corner of the country: Dr. Robert Nowinski of The Fred Hutchinson Cancer Research Center in Seattle.
Both hailed from New York. Both were brash and ambitious. And both saw potential riches in biotechnology.
The Bayh-Dole Act of 1980 had encouraged publicly financed scientists to patent their inventions, setting off a boom in biotech. Nowinski, who was 35 that year, wanted in, and Blech was holding the door open.
Blech asked Nowinski to head up Genetic Systems, and to bring some of his Hutch colleagues along. With their reputations, Blech knew they could create enough buzz around the company's stock that they would all get rich.
Genetic Systems incorporated on Nov. 13, 1980. In the next two months, Nowinski and Blech gave penny-a-share stocks to three key scientists at The Hutch:
** Don Thomas got 100,000 shares, a $3,000 annual stipend and a seat on the company's scientific advisory board.
** John Hansen got 250,000 shares and a job as the company's medical director. He would continue to work at The Hutch but promised to "devote such time as is necessary" to Genetic Systems for an $18,000 consulting fee.
** Paul Martin, Hansen's protégé and assistant, got 10,000 shares and a three-year exclusive consulting agreement with Genetic Systems.
Blech put together a prospectus touting the doctors and The Hutch. He raised $3 million in the first three months of Genetic Systems' existence, swelling the value of the doctors' stock holdings.
Thomas' presence on the prospectus was particularly important. At age 60, he had earned an international reputation.
An immunologist, Thomas had been involved in the world's first bone-marrow transplant, in New York in 1956. The patients, identical twins, had died, but the procedure had shown promise.
Marrow, a spongy tissue inside bones that produces blood cells, begins to die when cancer patients receive radiation and chemotherapy. The amount of damage to the marrow depends on the amount of cancer-killing material the patient receives. It limits how much treatment a person can survive.
Thomas and others believed that if marrow could be replaced through transplant, they could boost the cancer-killing treatment and then restore the patient's ability to produce new blood cells.
A bone-marrow transplant is a straightforward procedure. Marrow from a donor is infused through a catheter into a recipient's veins. If all goes well, the factory cells in the donor marrow, known as stem cells, lock in and begin forming new blood cells in the patient.
Thomas moved to Seattle in 1963. Between 1969 and 1974, he transplanted marrow into 54 patients with supposedly incurable leukemia. Most died, either from their cancer or from treatment complications such as infection. But six were cured.
In 1975, Thomas and other doctors opened the Fred Hutchinson Cancer Research Center, naming it after a former professional baseball player from Seattle who had died at age 45 from lung cancer. The Hutch specialized in cancers of the blood, and grew to perform some 450 bone-marrow transplants a year.
Worldwide, the procedure has been credited with saving more than 150,000 lives.
Meanwhile, Hutch doctors have conducted hundreds of clinical trials to advance the science. The Hutch receives more than $140 million a year in federal grants to pay for these experiments.
Controversial from the start
On Jan. 20, 1981 - two weeks after Thomas, Hansen and Martin received their founders' shares from Genetic Systems - the Human Subjects Review Committee at The Hutch met to consider a research proposal from those three doctors.
The doctors wanted to use money from the National Cancer Institute and leukemia patients from The Hutch in a new bone-marrow experiment, labeled Protocol 126.
The experiment would try to prevent an immune-system reaction known as graft-versus-host disease, or GVHD.
As many as half the recipients of marrow transplants from tissue-matched sibling donors suffered GVHD. At best, the disease was annoying, like a rash. At worst, about 5 to 10 percent of the time, it was fatal.
The researchers believed GVHD was caused by "T-cells" in the donor marrow. T-cells, so named because they mature in the thymus gland, are certain white blood cells that trigger the immune system to destroy foreign material and fight infection.
The researchers wanted to use newly manufactured drugs, known as monoclonal antibodies, to kill the T-cells. If it worked, they believed, the success rate of bone-marrow transplants would improve.
But first, they needed the approval of the Human Subjects Review Committee, which assessed the ethics of all human experiments at The Hutch. Congress had mandated that all medical research centers have such review panels.
In pushing their proposal, Hansen and Martin cited studies in which this therapy had been successful in mice. And, they said, the only known study with dogs had also been successful.
However, Dr. Rainer Storb, the Hutchinson Center's expert on GVHD, knew that at least one T-cell study on dogs had been unsuccessful, with some of the subjects dying in treatment. Although the results were not published, Storb said, they were widely known by those in the field.
Storb was not a member of the review committee, but he opposed Protocol 126. In doing so, he collided head-on with one of his fellow Hutch founders, Thomas.
"Don Thomas clearly favored this approach for whatever reasons ... " Storb said. "There was a feeling of not wanting to be left behind" other research centers.
Thomas, Hansen and Martin did not mention financial interests in Genetic Systems to Storb or the review committee. When Storb ultimately learned about those interests, he said, "It raised issues in my mind" and solidified his opposition to the trial.
First proposal is rejected
Most of the 11 members of the Human Subjects Review Committee were Hutch employees. Among them was Dr. Michael Kennedy, a specialist involved in the type of research proposed in Protocol 126.
In a recent interview, Kennedy recounted that he, too, had objected to many features of the proposed study. His objections in 1981 would presage the problems of the next dozen years.
The committee kept detailed minutes of its discussion. Hutch officials refused to make those minutes public, but The Seattle Times obtained them through a Freedom of Information Act request to the federal government.
The committee - whose members are identified by numbers rather than by name in these records - gave the proposal a largely negative reaction. Among their concerns:
** The lack of adequate prior research on animals. Normally, experiments of this type at The Hutch were performed extensively on mice, followed by studies of dogs before moving to humans.
"The jump from mouse to man is too great ... " said one committee member.
** Contrary to most such research, Protocol 126 proposed experimenting on the healthiest, rather than the sickest, patients. Some of them, whose leukemia was in remission, had a 60 percent chance of lifetime cancer-free survival with a standard transplant from a matched sibling donor.
** The proposed subjects for the experiment - those with siblings whose tissue type matched theirs - were the least likely to get GVHD, much less die from it.
** Some thought T-cell removal might actually prevent the bone marrow from engrafting, or taking hold in the recipient's body. Normally, graft failure is extremely rare, occurring in 1 out of every 100 marrow transplants.
Kennedy, in particular, thought T-cells were needed for new marrow to lock in and start producing healthy blood. And some thought T-cells helped prevent cancer relapse.
** The "informed-consent" form for patients minimized the risk of graft failure and made it sound as if a second transplant could be done without difficulty if the first one failed. In fact, second transplants were known to be fatal about 95 percent of the time.
** The consent form also failed to mention alternative treatments for GVHD.
Given all that, the committee voted not to approve Protocol 126. Hansen was told he could change it and reapply.
The experiment was revised to cut back the T-cell-killing power of the drugs and resubmitted. This time, the review team was headed by Dr. John Ensinck, an endocrinologist and Thomas' counterpart as head of clinical research at the University of Washington, where many Hutch doctors taught.
The committee voted on April 21 to approve the experiment. The minutes do not show why, and Ensinck couldn't recall specifically.
Ensinck, now retired, said in a recent interview: "At that point, I recall, The Hutch was doing uniquely experimental protocols at the cutting edge, so I recall we reviewed them very stringently."
Kennedy, who now has a private practice and teaches at the UW, says the committee's concerns were never addressed.
Again, committee members were not told that some of the drugs in the experiment - three of the eight antibodies ultimately used - were licensed to a company in which the researchers had a financial interest. Nor were they told that by that time, The Hutch itself had a monetary stake in the experiment.
In March, Nowinski had struck a deal with The Hutch to acquire the exclusive commercial rights to 37 specific monoclonal antibodies for 20 years. In return, Nowinski gave The Hutch 50,000 shares of stock, at least $125,000 in research funding, and agreed to pay the institution as much as 20 percent of royalties or 8 percent of net sales of the antibodies.
On the strength of that deal, Blech proceeded to raise $3.7 million from a pharmaceutical company and $2.6 million in two private stock offerings. The Hutch antibodies were the company's main assets. A written pitch to investors touted the development of antibodies to diagnose and treat infectious disease and cancer.
As Protocol 126 geared up, Genetic Systems raised an additional $6.6 million in an initial public offering. In its first quarter, the value of the stock the Hutch doctors had received was $875,000 for Hansen, $350,000 for Thomas, $35,000 for Martin, and $175,000 for the Hutchinson Center.
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, 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.
"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.
New theory on failures
By mid-1984, Martin and Hansen began to discuss their setbacks in seminars. An issue of the medical journal Blood includes an article in which they note the high graft failure in their experiment - 40 percent at that point - was "a highly unusual outcome."
But not, apparently, reason enough to end the trial.
The Blood article outlined their plan: While eight of 11 patients with the best prognoses had failed to engraft, only one of the other nine patients had failed. The authors theorized that the higher radiation given sicker patients had weakened the immune system enough to let the donor marrow take hold.
The IRB, still headed by Kaplan, instructed Martin to change the patient-consent form before Protocol 126 could proceed. "Specifically, the risk of loss of graft should be more clearly stated," the panel said.
The form being shown to patients said: "To the best of our knowledge, (Protocol 126) does not damage the cells necessary for engraftment."
A revised form conceded that the treatment "may damage cells necessary for engraftment," then continued with its previous assurance, "In this case, a second marrow transplant would be necessary."
Again, it didn't say that second transplants fail 95 percent of the time. It didn't say there was a higher risk of relapse, nor did it disclose the Storb alternative, nor the financial interests.
Pesando thought the IRB, under duress, had surrendered. And Pesando said they never knew at the time that Storb, too, opposed Protocol 126.
Kaplan, assured by president Day that there would be a scientific review and that the experiment would stop immediately if it had two more graft failures, approved Protocol 126.1, the next stage of the trial, on behalf of the IRB on June 1, 1984.
Those graft failures came quickly.
Dr. John Draheim, 36, a physician for the U.S. Navy in Bremerton, and Seci Cay, 31, owner of an export-import business in Turkey, came to The Hutch for chemotherapy, radiation and transplants in the fall of 1984. When their T-cell-depleted marrow failed to engraft in December, the trial was halted again.
Kaplan wrote Day "once again" objecting to the protocol on scientific and ethical grounds.
"Monoclonal antibodies are being used in what appears to be a completely uncontrolled fashion ... " Kaplan wrote. "Alternative therapy seems downplayed in importance. ... In addition, the board is concerned about authorizing protocols in which the apparent successful use of an agent could be potentially beneficial financially to many of the investigators listed on the study."
Dr. Frederick Appelbaum, head of the clinical-research division, replied on Day's behalf, telling Kaplan to stop complaining about financial conflicts. He said the IRB must either express concern about all types of financial conflicts, such as the possibility of researchers losing their jobs if patients stopped enrolling in the experiments, or "accept the fact that those of us in cancer research are intrinsically honest individuals who are trying our best."
Martin proposed further human experiments. Admitting "graft failure represents a highly unusual outcome," Martin said he would add methotrexate, one of the drugs Storb was studying, to aid engraftment.
In January 1985, the IRB approved Protocol 126.2, the next stage.
Two weeks before that approval, Draheim died, with Hansen himself the attending doctor. Two weeks afterward, Cay died. They were at least the eighth and ninth victims of graft failure caused by the treatment.
"Each successive protocol was a variation on some aspect of the treatment, with the goal of asking would this change make a difference in the outcome," Martin said later. "And recurrently, the answer was no."
In other words, no matter what they tried, the treatment wasn't helping patients.
`She never got better'
Elizabeth Almeida, 35, was a strong-willed single woman about to adopt her foster child, a 13-year-old boy, when she was diagnosed with leukemia.
While the first patients were dying of T-cell depletion in Seattle, she was undergoing chemotherapy in Boston, about an hour from her home in New Bedford, Mass. The cancer disappeared, then re-emerged, then disappeared after more chemo, but the prognosis was grim.
Her doctor told Almeida that her best chance for survival was a bone-marrow transplant at the Hutchinson Center in Seattle. She had a perfectly matched sibling, James, to donate bone marrow. If she could survive even more chemotherapy and radiation, James' donated blood could help her start manufacturing new, clean blood.
Almeida and her mother and brother traveled across the country in March 1985. In a conference with a Hutch doctor, they were offered the "informed-consent" documents for Protocol 126.2.
That form had not been updated as the IRB had ordered, a technical violation of federal human-protection rules. Again, it described graft failure as merely possible and correctable, and failed to mention the higher risks of new or recurring cancers.
Though Protocol 126 was a highly experimental procedure, the statement of risks on the patient-consent form was more serene than the warnings on many drugstore medicines.
The Times, with the family's permission, obtained Almeida's 1,833-page medical file. It offers no evidence that anyone ever told her or her family about the then-obvious risks of dying from the treatment, nor of the availability of Storb's more successful alternative treatment.
After some initial hesitation, and after being promised a conference with Martin, which she never got, Almeida agreed to participate in the experiment. She entered Swedish Medical Center in outward good health, with her disease in complete remission.
"Delightful," a nurse described her. "Looks well."
After a week of drugs and radiation, she grew weak and nauseated, then developed severe mouth pain, fevers, pneumonia and kidney failure.
Transplants have been compared with killing patients and then bringing them back to life. Almeida never came fully back. Her marrow never did restore its blood-making capacity after she got her brother's cells.
She recovered enough to return to Massachusetts, but the transplant ultimately failed to engraft and the leukemia returned.
"She never got better," Billy Tatro, a longtime friend, recalls. "When it was obvious the transplant was failing, it really wasn't apparent to anyone why. The doctor said there was only one possibility, and that was a second attempt. So he sent her back to Seattle."
Almeida was pale, frail and feverish when she checked back into Swedish.
"Bright, frightened woman," a social worker wrote.
She never got the second transplant. She died first, on Oct. 3, 1985.
Annmarie Ridings of Mattapoisett, Mass., didn't know her sister Elizabeth had been part of any experiment, let alone one with such a grim record.
"As you can imagine, this information has upset my family," she says.
"My family continues to feel the effects of her death fourteen years ago. I do not believe that my sister would have agreed to participate in a study that she knew had such a high failure rate."
A 100 percent risk of relapse
Among the people Elizabeth Almeida had met in the leukemia ward were the couple from Alabama, Pete and Becky Wright.
Becky was a mother of three, a runner, a dancer, who had been diagnosed with chronic myelogenous leukemia in March 1985. Like Almeida, she and her husband came to The Hutch for the best treatment money (about $200,000) could buy.
Dr. C. Dean Buckner discussed treatment options with the Wrights. His dictated notes were released by Swedish Medical Center with permission of Pete Wright.
Buckner told Becky she would not be cured by conventional chemotherapy, but stood a good chance of survival with a bone-marrow transplant. More than half the patients with diagnoses similar to hers were still alive after getting transplants, he said.
Buckner predicted only a 15 percent probability of leukemia recurring over the next two to three years for Becky. However, he added, she had "high probability" of getting GVHD because of her age, 37, and he suggested she enlist in Protocol 126.
Pete Wright recalls: "We had been out there for a month waiting for a bed, and I remember talking about the protocol. We were told this was the best way to avoid GVHD, and from some of the pictures we'd seen and the things we'd heard, we definitely wanted to avoid that."
The consent form the Wrights were given emphasized the benefits. Under "Risks," it said: "Graft rejection has occurred following such treatment. In this case, a second marrow transplant would be necessary."
Pete Wright says - and the records indicate - that Buckner mentioned the risk of graft failure but did not say that more than a quarter of the transplants in Protocol 126 so far had failed. Nor did he say that second transplants were 95 percent fatal. He apparently did not mention the risk of relapse or new cancers at rates significantly higher than in standard transplants.
Buckner now says he was "one of the bigger skeptics" about Protocol 126 but "I didn't find anything unscientific or unethical about any of this. We were all trying to make people better. And at that time, it was felt that T-cell depletion was the greatest thing since sliced bread. And it wasn't."
In fact, as Martin, Thomas, Buckner and other Hutch doctors outlined in a journal article on chronic myelogenous leukemia published three years later:
"The actuarial relapse risk 2.5 years posttransplant was 100 percent in patients administered T-cell-depleted marrow as compared with 25 percent in patients administered unmodified marrow."
A 100 percent risk of relapse. Every patient like Becky Wright, if he or she lived long enough, saw the nightmare of leukemia return.
The statistic shocked Pete Wright when he saw it years later. The relapses in Protocol 126 included eight patients before Becky walked in the door, and six afterward. She was not the only one, nor was she the last.
Pete Wright said Becky didn't give much thought to the protocol, trusting doctors to act in her best interest. She signed most of the forms before even talking with Buckner.
"She knew this was her one shot to live," Pete Wright said. "She was upbeat. She was psyched up and ready to go."
`The pain never really dies'
Becky Wright told Pete she never imagined she would feel so bad.
Chemotherapy not only kills cancer cells, it assaults normal tissue in hair follicles, the mouth, the digestive system and the bone marrow. Wright suffered painful lesions, systemic infections, diarrhea, organ damage.
But if she could be cured, it would be worth it.
On June 17, 1985, she received her sister's marrow, which had been treated with the eight antibodies and was devoid of T-cells.
She was luckier than some: The graft took; her white cells propagated and her sores and infections healed. Becky Wright checked out of the hospital a month after the transplant and flew home to Heflin, where life more or less returned to normal.
But when she flew back to Seattle the following year, a checkup showed her leukemia had returned. Doctors recommended a second transplant, this time with T-cells. She got it, but was too weak to survive a graft-versus-host reaction and bloodstream infections.
"I can hardly take deep breaths; it's too painful," she told a nurse.
She missed her children. She wanted to go home to Heflin. There was nothing The Hutch could do to help her. And on the day before Mother's Day, 1987, Becky Wright hemorrhaged and died in a hospital bed in Birmingham, Ala.
Whether she would have survived with standard treatment will never be known. But based on the evidence, her widower feels his wife was deprived of her optimal shot for survival.
At the very least, he said, they were deprived of crucial information they deserved to know.
Earlier this year, Pete Wright was shown Pesando's letters and studies on T-cell depletion. The understated risks and undisclosed financial interests infuriated him.
"My grandfather was a doctor, an active doctor for 62 years," Wright said. "He would be doing back flips in his grave if he heard about this."
Pete Wright is remarried and trying to move on with his life. He doesn't want Becky's ghost to haunt his new family. But he says, "The pain never really dies. The truth definitely needs to come out on this."
The experiment ends
In October 1985, Bristol-Myers bought Genetic Systems for $294 million, or $10.50 per share. The purchase raised the value of Hansen's original stock holding to $1.8 million, Thomas' to $1.05 million, Martin's to $105,000 and The Hutch's to $502,000.
Protocol 126 lasted 12 years - an extraordinarily long time for a clinical trial - even as deaths mounted.
Each new phase tested slightly different combinations of chemotherapy, radiation or immune-system suppression, but all were built around the same antibodies.
The later versions of Protocol 126 ended with graft failures in two of 12 patients, two of nine, two of eight, two of nine, two of two, and one of one, respectively. Overall graft failure was at least 24 percent, vs. the expected 1 percent.
And even when the transplants took, the cancer came back. Of those with chronic leukemia, 100 percent suffered relapses, vs. the expected 25 percent.
As the failures mounted, the description of the study in filings with the National Cancer Institute changed: It began as an experiment in whether T-cell depletion would prevent GVHD. It ended as an experiment that showed T-cells were necessary to engraft and to fight spare leukemia cells.
The consent form in the final phase of the study, approved by The Hutch in 1991 and 1992 for up to 20 patients, warned that patients "often reject the marrow," leading to death, and that T-cell removal "may increase the risk of relapse."
Finally, it revealed: "In this situation, there is a high chance of infections, bleeding and death."
The first patient in the final phase, a 30-year-old man with a mismatched donor, experienced graft failure. The protocol was ended forever.
Records reflect that at least 20 patients died from graft failure in the experiment between 1981 and 1993. The first seven of those had forms of cancer with a cure rate of about 50 percent with standard treatment.
In the end, the experiment was almost uniformly fatal.
Martin, Hansen and Thomas never did write a final report on Protocol 126. Martin says he discarded his files when he moved to a new office in 1998.
But Martin disclosed the final toll: 82 people from around the world enrolled in the Seattle experiment; 80 of them are dead today. And the Hutchinson Center has become a leading voice against T-cell depletion.
"We worked very hard to remove every T-cell from the graft and we found out that wasn't a bright thing to do," Martin says now.
He wishes he had set up a better mechanism for ending the stages of the experiment as they proved unsuccessful. He blames his inexperience, and a lack of guidance from The Hutch.
"I don't know that I was trained as well as I would have liked at the time," he says. "Nobody told me what to do."
Martin passionately insists, though, that his persistence down the path of T-cell depletion was motivated by science, not by business.
"I want to assert definitively that the clinical trials were motivated by scientific evidence suggesting that the results of bone-marrow transplant could be dramatically improved by removing the T-cells from the graft," he said.
Martin's mentor, Hansen, is less emphatic in his denial of financial motivation. Asked whether the doctors' personal investment in Genetic Systems affected the experiment, he replied: "I don't think so. I don't think so."
Asked if Genetic Systems stood to make money if the antibodies proved successful, Hansen said: "Well, of course that was the idea. You start a company to make a profit."
Duff Wilson's phone number is 206-464-2288. His e-mail address is dwilson@seattletimes.com.
David Heath's phone message number is 206-464-2136. His e-mail address is dheath@seattletimes.com.