Copyright © 2001 The Seattle Times Company

Local News : Sunday, March 25, 2001

On March 11, 2001, The Seattle Times began a five-part investigative series entitled, "Uninformed Consent: What patients at 'The Hutch' weren't told about the experiments in which they died." In it, Times reporters David Heath and Duff Wilson described how patients had died prematurely in two clinical trials at Seattle's Fred Hutchinson Cancer Research Center, experiments in which some of their doctors and the center itself had a financial interest.

As The Times documented, the patients weren't told about those financial ties, nor were they fully informed about the medical risks of the experiments.

Since the series was published, officials at "The Hutch" - using their Web site and a series of newspaper advertisements - have raised questions about the fairness and accuracy of the series. Although feedback from readers and from the medical community in Seattle and elsewhere has been overwhelmingly supportive of the reporting, some people - especially employees of The Hutch, their families and some patients who have been successfully treated there - have sent letters and e-mails to The Times with complaints and questions about the stories.

Reprints of the 'Uninformed Consent' series available Reprints may be picked up for free at The Seattle Times' main office, 1120 John Street, or at our Eastside Bureau, 10777 Main Street, Bellevue. A copy can also be mailed to you for $2. Call 206-464-3113 to order. Checks and credit cards accepted.

Here are some of the issues they raise, and answers from Times editors and reporters:

Overview

A: The Hutch's groundbreaking work in cancer research was noted repeatedly throughout the series. On the first day, a separate story recounted the history and accomplishments of the center. Further, the good works of The Hutch have been covered thoroughly by The Times in the center's quarter-century of existence. More than 1,400 Times stories have mentioned the center, almost exclusively in positive contexts. The paper has published nearly 500 stories about medical developments at The Hutch.

Q: But why did you have to write such a negative story this time?

A: We didn't set out to write a "negative story." Rather, we set out to answer serious questions brought to us by two unconnected sources: a doctor who had tried to stop one of the clinical trials from the inside, as a member of a Hutch review board, and an attorney whose mother had died in the other clinical trial. Reporting done over many months, interviewing hundreds of people and reviewing thousands of documents, showed those questions to be legitimate ones.

Raising them publicly became particularly important as clinical researchers, government officials and medical ethicists begin to consider and debate whether medical experimentation is adequately regulated in this country. Central to that debate are some of the very issues raised in this series: what patients deserve to be told about the financial connections of medical centers and doctors to for-profit drug and biotechnology companies.

Q: Why did you decide to publish this story now? Was it, as Hutch officials claimed, that you published it during your "sweeps week," the week newspapers count their circulation numbers?

A: Newspapers have no such "sweeps week." Newspaper circulation is calculated as a daily average over a six-month period. The current period ends March 31.

This was not about selling newspapers any more than any of the journalism we do here - from coverage of the Legislature to international news to movie reviews to Mariner game stories - are about selling newspapers. It was about our commitment to serving the community through quality journalism.

Two things drove the timing of the series: First, it was ready to be published after more than a year of reporting and research. Secondly, Congress is considering whether medical-research laws should be reformed, and a federal blue-ribbon panel is meeting this spring to work on the issue. We felt this reporting could contribute significantly to that conversation, and considered it our responsibility to add it to the public dialogue.

Last week, that belief was reinforced by Dr. Mary Faith Marshall, chairwoman of that panel, called the National Human Research Protections Advisory Committee. She specifically cited The Times' stories as "incredibly important" in the process and said it was "a golden moment" for reform.

Q: But the president of The Hutch, Dr. Lee Hartwell, said in a news conference that some of your fundamental findings were "blatantly false."

A: Yes, he did. But in that news conference and subsequently, Dr. Hartwell has offered very few specific refutations. The few specific matters he and others have raised are addressed below. And in a conversation with Times editors, Dr. Hartwell acknowledged that the stories revealed a problem with the appearance, if not the reality, of conflicts of interest at The Hutch.

Q: Hutch officials say that for the patients in these clinical trials, the experiments were a "last hope" for survival. You reported that some of the patients had a good chance of survival with conventional treatments. Which is true?

A: There were two experiments covered: a blood-cancer experiment conducted from 1981 to 1993, and a breast-cancer experiment conducted from 1991 to 1998. Some of the patients in the blood-cancer experiment had a 50 percent or better chance of survival with a conventional bone-marrow transplant - that is, without the experimental depletion of certain white blood cells. Others had a 10 to 20 percent chance of a cure.

Most of the patients in the breast-cancer experiment would likely have died within two or three years, but some died faster because of the treatment.

Q: Hutch officials say you, who are not medical professionals, simply didn't understand some technical aspects of these trials. What did you do to ensure accuracy?

A: It's true the reporters who wrote these stories are not doctors. But we interviewed dozens of them, both at The Hutch and elsewhere, in the course of doing these stories. And when we were ready to publish, we had the stories reviewed for technical accuracy by a nationally regarded bone-marrow specialist from a major research institution.

Q: What have you heard from other medical professionals not associated with The Hutch about the stories?

A: The reaction has been overwhelmingly positive. Many local medical professionals - including officials at the University of Washington, Virginia Mason Medical Center and Children's Hospital and Regional Medical Center - have contacted The Times to express their support of the stories. However, some doctors and academics have written to criticize what they felt was an unfair attack on The Hutch.

Conflicts of interest

A: No. The stories never pretended to know the researchers' motives. We did report that these doctors held stock in companies that had a financial interest in drugs being tested in these experiments, thus placing themselves in a position of actual or possible conflicts of interest.

We also quoted some of these doctors as insisting that they were driven not by making money, but by trying to cure cancer.

Q: Dr. Hartwell doesn't seem concerned about conflicts. Why should we be?

A: Financial conflicts of interest can affect research integrity and public confidence in science and medicine. Several highly regarded studies, including some published in The New England Journal of Medicine, have documented that financial ties to medical experimentation can have an impact on the results.

Also, there is evidence that Dr. Hartwell is, in fact, concerned about such issues. When he became president of the center, he divested himself of his own stock holdings in a biotech company, turning them over to The Hutch. He did so, he says, to remove any appearance that he might be favoring studies in which that company had an interest.

Q: But isn't it unreasonable to expect that doctors and research centers won't have partnerships with biotech companies?

A: Most major medical-research centers these days do have such partnerships. In fact, such arrangements were encouraged by Congress in the Bayh-Dole Act of 1980. But two decades later, many people in the field think the associations should be better regulated and policed.

Q: Do other research institutions handle financial connections and disclosure differently?

A: Yes. A number of research centers, including the prestigious Memorial Sloan-Kettering Cancer Center in New York, do more to discourage and limit connections with private industry. Others disclose their financial ties to for-profit companies on patients' informed-consent forms. The Hutch itself meets the minimum standards required by the National Institutes of Health. The Hutch makes no disclosure to patients and keeps much of its own holdings and those of its doctors private, citing personal privacy and corporate confidentiality.

The blood-cancer experiment

A: Until the past two weeks, The Hutch consistently referred to Protocol 126 as The Times did: a single experiment, with different stages. The fundamental goal of the experiment remained the same in every stage: using eight antibodies - including three licensed to Genetic Systems, a company in which Hutch researchers had financial interests - to kill white-blood T-cells in bone marrow donated by tissue-matched siblings.

The researchers thought that eradicating the T-cells would eliminate a condition called graft-versus-host-disease, thus making transplants more successful. In fact, though, with the T-cell eradication, the rate of rejection of donated marrow and of the relapse of cancer both increased dramatically.

Relatively small changes in each stage included more radiation, more focused radiation, and different chemicals to try to enhance engraftment. John Pesando, the doctor who tried to stop Protocol 126, says those stages should have been performed on mice, rabbits or dogs - not people - after the first stage failed.

The Hutch's 24-page reply to federal investigators looking at the medical and ethical soundness of the experiment in 1993 never described Protocol 126 as eight separate experiments.

Q: Dr. Fred Appelbaum, the clinical-research director, said only three patients died of graft rejection before the informed-consent form was changed to clearly inform patients of the risk. Is that true?

Dr. Paul Martin, the principal investigator, said eight out of 20 patients in the first major phase of the experiment suffered graft failure. One recovered; seven died.

The patients, most of whom had a 50 percent chance of a cure with a regular transplant without the T-cell experiment, died between 37 days and 311 days after their first transplants. Martin said the expected rate of graft failure was 1 percent versus the 35 percent that occurred.

It is impossible for us to tell whether the patient-consent form for the next stage of the experiment was changed after the first three of these deaths because a full report on Protocol 126 showing dates and outcomes was never written. However, the families of patients involved in later stages, as well as some doctors on The Hutch's Institutional Review Board at the time, thought the consent form did not accurately portray the risk.

The first consent form said: "To the best of our knowledge, treatment of marrow with monoclonal antibody and rabbit serum does not damage the cells necessary for engraftment, but it is possible that engraftment will not occur following such treatment."

The revised form said: "Treatment of marrow with monoclonal antibody and rabbit serum may damage cells necessary for engraftment, and it is possible that failure of engraftment or graft rejection may occur following such treatment."

The next sentence in each form was: "In this case, a second marrow transplant would be necessary." Neither form indicated that second transplants were rarely successful.

Q: Dr. Appelbaum also says that The Times exaggerated the risk of failure of a second bone-marrow transplant. What about that?

A: Dr. Appelbaum referred to a study of second transplants after relapses of cancer. But the patients in that study had better prognoses than the graft-failure victims in Protocol 126. The patients in that study, unlike the graft-failure patients in Protocol 126, had time to recover from the ravages of chemotherapy and radiation.

The Times article referred to second transplants after graft failure, a dire situation in which patients' immune systems are weak and they are highly susceptible to infections and other fatal complications. Transplant experts say these "salvage transplants" were fatal at least 90 to 95 percent of the time in the 1980s and remain nearly that much today.

In Protocol 126, of the first six patients who had graft failure and lived long enough to try a second transplant, all six died. These were people who had a 99 percent chance of bone-marrow engraftment and a 50 percent chance of lifetime cure from their cancer with the standard treatment, without the secondary experiment in T-cells.

Despite the high failure rate in second transplants, The Hutch failed to change its "informed-consent" for subsequent patients, assuring them this was the solution if their first graft failed. Eventually, the consent-form was changed to describe second transplants as "potentially fatal."

Only in 1993, 12 years after the study started, did the patient-consent form say frankly, "Patients often reject the marrow. ... In this situation, there is a high chance of infections, bleeding and death."

Q: Dr. Appelbaum says there was "no possibility" of financial benefit for The Hutch or its doctors in this experiment, because another company held the patents on the key drugs and their uses. Is that true?

A: No. The Hutch and Genetic Systems could have benefited if the experiment had been successful. And the fact that monoclonal antibodies licensed to Genetic Systems were part of a clinical study at an institution as respected as The Hutch almost certainly had a positive impact on the company's value.

Three of the researchers on Protocol 126 - Dr. Martin, Dr. E. Donnall Thomas and Dr. John Hansen - had stock and other financial ties to Genetic Systems. The financier who started the company, David Blech, touted their involvement as he raised millions from investors.

As for the matter of a patent, timing is key. The patents covering uses of monoclonal antibodies - man-made proteins that zero in on foreign material - were filed by two scientists and Ortho Pharmaceutical in 1979. The U.S. Patent & Trademark Office was required by law to keep the filings secret, and the property rights would not be valid until the patents were issued.

In the first three months of 1981, as T-cell depletion suddenly became a hot property, Hansen, Thomas and Martin submitted Protocol 126 to The Hutch, took personal stock in Genetic Systems and helped arrange a deal where The Hutch gave Genetic Systems an exclusive commercial license to 37 monoclonal antibodies in return for royalties. Three of those antibodies were among the eight tested in Protocol 126.

The Ortho patents were issued Nov. 30, 1982, and Dec. 14, 1982 - more than a year and a half after The Hutch deals were under way.

While those patents then would reduce profit potential, they would not eliminate it.

Robert Blackburn, one of the nation's leading experts in biotech patents, was not specifically aware of Protocol 126, but he said if the experiment had succeeded, the inventors could have filed for what is known as a method or use patent that could co-exist with the Ortho patents.

"Other people may invent other ways of using (antibodies) such as using them for graft-versus-host-disease (GVHD), and they can get a patent on that treatment. That doesn't infringe on Ortho's method patent, which is typing blood cells, but it does infringe on their patent on the antibody per se," Blackburn said.

The method-patent holder and Ortho would have strong financial incentives to negotiate a license deal to be able to make money on the new method, said Blackburn, who is a visiting scholar at the University of California Center for Law and Technology and vice president and chief patent counsel for Chiron, an $8 billion California biotech firm.

Asked whether a method for preventing GVHD with monoclonal antibodies could present a good commercial opportunity, Blackburn said, "Obviously, yes."

The question of financial gain from drug sales became moot as Protocol 126 failed. At least 20 people died from causes attributable to the antibody treatment.

Financier Blech said he didn't know anything about Protocol 126. But if the deaths from it in 1983 and 1984 had been disclosed publicly, Blech said, it could have adversely affected the price of the company's sale to Bristol-Myers in 1985.

Genetic Systems sold for $294 million, or $10.50 a share, making the original stakes of the Hutch doctors worth about $2 million for Hansen, $1 million for Thomas, and $100,000 for Martin. If they held their Bristol-Myers stock - and only Hansen will say he did; Martin and Thomas will not comment - their stock value has gone up more than tenfold since then.

The shares they received for a penny apiece in 1981 are worth $108 today. Hansen's shares are worth $19.2 million; Thomas' and Martin's, if they kept them, are worth $10.8 million and $1.1 million, respectively.

Q: Hutch officials say that when this experiment began, they had no idea that graft failure might result. How could they have been expected to warn patients of it if they didn't know it would happen?

A: Graft failure was identified as a risk before the experiment began. Dr. Michael Kennedy, a member of the internal board charged with assessing patient safety in Hutch clinical trials, said in a review of the first application for Protocol 126 that the panel needed to balance the chance of dying from GVHD with the chance of dying from graft failure.

According to a transcript of a January 1981 meeting, Kennedy said, "whether (the treatment) would decrease chances for a graft is of serious consideration. These are patients who are in remission and not at real high risk for GVHD much less dying from the disease. ... You are looking at a fairly small percentage of probability of dying and I would want to know what is the risk of not getting a graft and dying to balance this decision."

He asked that possible graft failure be highlighted in the patient-consent form and the "inability to provide a second graft before overwhelming infection sets in needs to be elaborated on."

The panel rejected the protocol and told Hansen to highlight the risk of the first graft failing and the risk of the second graft failing. Hansen in April 1981 replied that he would cover "more directly the potential risk of graft failure and details of what a 2nd marrow transplant would involve."

The patient-consent document then said, "To the best of our knowledge, treatment of marrow with monoclonal antibody does not damage the cells necessary for engraftment, but it is possible that engraftment will not occur following such treatment."

By then, the members of the review committee, notably Kennedy, had changed. The committee approved the protocol.

Q: You reported that the strategy of depleting T-cells as part of bone-marrow transplants was a failure. But Hutch officials say this technique is still being used at many medical centers today.

A: A partial depletion of T-cells is still used in many centers performing bone-marrow transplants, notably Memorial Sloan-Kettering. They do not kill virtually all of the T-cells, as The Hutch did in its experiment. They have learned that some T-cells are needed to allow engraftment and fight cancer relapses.

The Hutch, meanwhile, has become the leading transplant center that does not do any T-cell depletion work.

Q: Hutch officials say the Institutional Review Board, the internal body charged with overseeing human experiments at the center, acted "forcefully and effectively." Is that true?

A: No. The Institutional Review Board (IRB) did vote to allow variations of Protocol 126 to proceed, but IRB members say they were misled. For instance, federal law required deaths and other unexpected setbacks to be reported to the IRB; they were not. Federal regulations require good record-keeping of IRB decisions so later IRBs can make informed decisions; the detailed and prescient concerns of the IRB in 1981 (including a transcript) were not provided to later IRBs.

Dr. Pesando, an IRB member who objected to Protocol 126 (and who ultimately came to The Times with this story), says he was intimidated and misled by Hutch officials who controlled his career.

Dr. Robert Bruce, a University of Washington medical professor emeritus, calls his experience on the Hutch IRB "the most difficult, frustrating and unsatisfactory of all the professional committee involvements I have had over the course of four decades."

Dr. Henry Kaplan, a highly respected Seattle oncologist, tried time after time to get Hutch administrators to set up a completely independent scientific-review committee for the monoclonal-antibody experiments, but they refused to do so.

Q: Hutch officials say concerns over this experiment were thoroughly investigated by the federal government, and The Hutch was exonerated. Wasn't that sufficient?

A: Neither part of that statement is true. The investigation was not thorough - which even federal officials who worked on it now acknowledge - and The Hutch was not exonerated.

The federal investigators didn't visit The Hutch or interview any scientists, Institutional Review Board members, patients or patients' families. The investigation was dropped in midstream, because of staffing shortages, and a letter making the narrowest possible findings - and blaming the IRB itself for not doing more - was sent to The Hutch.

Rather than exonerating The Hutch, the letter found "no material failures" under a narrow reading of federal law.

The final letter from Dr. Thomas Puglisi, chief of the compliance oversight branch of the federal Office for Protection from Research Risks (OPRR), added that "it is not acceptable that the IRB be responsible for obtaining information about research outcomes which might influence its continued approval of ongoing research."

On Friday, Puglisi, who recently left the government, issued this statement:

"OPRR did not believe it had the authority to rule unilaterally on conflict-of-interest issues. In retrospect, I think we should have pushed more vigorously to define acceptable standards. If we had done so then, perhaps clear conflict-of-interest standards would have been implemented by now."

The breast-cancer experiment

A: Nothing was said about a prior death in the informed-consent document Kathryn Hamilton signed. No mention of the prior death is made in the doctor's notes about the informed-consent conference with Hamilton. Allan Berman, Hamilton's husband, and Chris Addicott, her son, said nothing was said about prior deaths in the informed-consent conferences doctors held with Hamilton and her family.

At The Hutch's press conference, Dr. Frederick Appelbaum said that a review of all notes from Hamilton's informed-consent conferences show that a risk of death was discussed, which is accurate but does not contradict anything reported in the series.

Q: The Hutch says that patients were told in depth about studies showing that a rescue drug, pentoxifylline or PTX, had negative results. Again, why did you report that Kathryn Hamilton hadn't been told?

A: The informed-consent document inaccurately said that recent studies showed that PTX was successful in protecting patients from high doses of chemotherapy. The one study that showed positive results had been dismissed a year earlier by the very scientist who led that study.

Dr. James Bianco, the scientist who led the study and started Cell Therapeutics to develop and sell a drug combination that included PTX, said in a taped interview, "In 1991 when we started, we, for all intents and purposes, in our minds, had pretty much written off pentoxifylline by itself."

Hamilton was told in January 1993 that PTX by itself was effective. Yet by then, two other studies, including a large, controlled study done at The Hutch, showed that the drug didn't work.

Neither the informed-consent document nor the doctor's notes of the informed-consent conference mentioned negative findings on PTX. Furthermore, the protocol given to the Hutch's Institutional Review Board to justify the trial and even a later modification of the protocol mentioned nothing about negative findings on PTX. Family members insist this information was not provided to Hamilton.

Q: The Hutch justifies escalating the dose of chemotherapy it gave patients, saying that the death rate in the breast-cancer study was as expected. What about that?

A: The study was intended to find the "maximum tolerated dose" of two chemotherapy drugs for metastatic and advanced breast-cancer patients. It was not designed to see whether the drugs would prolong the life of patients. The Hutch says that its protocol allowed researchers to keep escalating the dose unless two patients died or suffered life-threatening complications.

That puzzles numerous drug-development experts, oncologists and medical ethicists interviewed by The Times. Alexander Capron, director of the Pacific Center for Health Policy and Ethics at the University of Southern California, said, "If you've reached a lethal dose, you would think that you would not need double proof of it."

None of the experts had ever heard of a clinical trial in which doses were escalated after a patient died from the drugs.

The series reported that for all dose-escalation cancer trials, the mortality rate from the drugs being tested was 1 in 200.

The Hutch says that the rate is higher for high-dose chemotherapy for breast cancer. In a recent letter to The Times, Dr. C. Dean Buckner, who was one of the doctors involved in Protocol 681, said that six of 68 patients in the breast-cancer study died from complications of treatment, for a 9 percent mortality rate. Some other high-dose chemotherapy studies had similar mortality rates.

However, a major, controlled study of 553 patients led by Dr. Edward Stadtmauer of the University of Pennsylvania, done during the same time as the Hutch's dose-escalation study, reported a treatment-related mortality rate of less than 1 percent.

Q: The Hutch says that the study was not originally designed to include an intravenous form of a drug. Yet the story stressed the point that Hamilton didn't receive the IV. What is the significance of this?

A: The fact that the study was not originally designed to include the intravenous form of PTX is irrelevant to Hamilton's family. Her son, Addicott, says that the availability of an IV form of PTX - stated on her informed-consent form - was critical to his mother's decision to enter the study. She was very anxious about throwing up pills, as she had done during previous chemotherapy.

As the story reported, Addicott remembers telling his mother, "They're giving you a lethal dose of chemotherapy, and unless you get the PTX, you could die. But you should be OK because if you can't keep the pills down, they'll give you the PTX in intravenous form."

Hamilton did indeed repeatedly throw up the PTX pill and finally refused to take it anymore. She was never given the IV version.

"I think that's what bothers me so much about this," Addicott says now. "She was relying on me to help interpret and understand the science of what was going on. I did that, and I think I did it correctly. But I think I was given wrong information."

Appelbaum now admits that telling Hamilton the IV would be available was an error. "We feel very badly that in this one case there was the mix-up."

Q: The Hutch says that patients could stop taking the drugs whenever they chose. So couldn't Hamilton have just withdrawn from the study when she didn't get the IV?

A: In the first three days of her care, Hamilton was given lethal doses of a chemotherapy drug called busulfan. Had she withdrawn from the study, she would have died. So withdrawing from the study was not a real option.

The future

A: Indications abound that regulation of human clinical trials will be reformed, both nationally and at The Hutch.

On Friday, Hutch officials announced formation of a blue-ribbon panel of outside experts, patient advocates and community members to review the way it handles financial conflicts and informed consent.

Meanwhile, the National Human Research Protections Advisory Committee meets again next month. It will take its recommendations to the secretary of Health and Human Services.

And Congress is expected to take up these issues later this spring.