|Patients never knew the full danger of trials they staked their lives on
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By Duff Wilson and David Heath
Seattle Times staff reporters
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Copyright © 2001 The Seattle Times Company
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 - had financial ties to 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.
Becky and Pete Wright leave the hospital after her first bone-marrow transplant, in 1985.
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 promised the center a percentage of royalties on sales of the antibodies. Simultaneously, he signed a deal with the Hutch-affiliated Pacific Northwest Research Foundation the parent from which The Hutch was founded and, like The Hutch, headed at the time by Dr. William Hutchinson that would give Genetic Systems the rights to new antibodies developed by Hutch doctors in exchange for 50,000 shares of stock and at least $125,000 in research funding.
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.
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 foundation.
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100,000 shares Genetic Systems Co. stock for Dr. E. Donnall Thomas, April 1983 (700K PDF)
250,000 shares of stock and position for Dr. John Hansen, April 1983 (852K PDF)
10,000 shares of stock and consulting agreement for Dr. Paul Martin, Jan. 1981 (524K PDF)
Investment prospectus touts company ties with The Hutch, June 1981 (3.2MB PDF)
First application of Protocol 126 to Human Subjects Review committee, Dec. 16, 1980 (580K PDF)
Committee minutes and transcript, Protocol 126 rejected, Jan. 20, 1981 (1.8MB PDF)
Drs. Polissar and Ensinck comments on Protocol 126, April 6, 1981 (2MB PDF)
Genetic Systems paid cash and stock for Hutchinson antibody rights, March 31, 1982 (824MB PDF)