By Duff Wilson and David Heath
Seattle Times staff reporters

Copyright © 2001 The Seattle Times Company

Dr. John A. Hansen kept about $10 million stock and broke conflict-of- interest policy	Dr. E. Donnall Thomas took stock worth $5 million today, if he kept it, which he won't say. Donated the $350,000 for his Nobel Prize to The Hutch.
Dr. Robert Nowinski started three big biotechs. Sold one to Bristol-Myers for $295 million.	Dr. James Bianco owns $5.1 million stock after two products flopped then a third took off.

THE INTERNATIONAL reputation of Seattle's Fred Hutchinson Cancer Research Center was forged with a courageous and sometimes defiant approach to conventional medicine.

It was built by doctors empowered to try new weapons against cancer, even if it meant some patients might die sooner than they would have with conventional treatments.

The center's most respected researcher, Dr. E. Donnall Thomas, won a Nobel Prize for persevering on bone-marrow transplants despite the doubts of peers and the deaths of patients. In his seminal work between 1969 and 1974, he performed bone-marrow transplants on 54 cancer patients. Forty-eight died, but six lived.

In the quarter-century since, "The Hutch" has continued to improve those methods, which have saved thousands of lives around the world.

But now, in the wake of articles in The Seattle Times this week, some doctors, medical ethicists and patient advocates are questioning whether the swagger that put The Hutch on the map in the 1980s and '90s has created a culture that is unduly insulated from public accountability.

The Hutch's approach to ties with industry, its policies on financial disclosure and its stance on public access to its activities, while not unique, differ significantly from those at some other respected institutions.

The result: a system in which patients pondering whether to enter a clinical trial may have little information - and little choice but to trust the center, even when financial connections might raise legitimate questions about the experiments on which they're betting their lives.

"The issues that are raised in this (series), whether they occurred 10 years ago or today, are of critical importance in our system of human research," said Dr. Greg Koski, director of the federal Office for Human Research Protections.

Nowhere is the combined success and secrecy of The Hutch so plain as in its partnerships with biotechnology companies.

As The Times has outlined, the center and many of its doctors, including Thomas, have linked their research to the for-profit business world of biotech, spinning off private companies worth more than $18 billion today and producing some $100 million in personal wealth.

Those financial relationships create the potential for conflicts of interest in the conducting of human experiments. But patients and the public have had little opportunity to even ask such questions, let alone to have them answered.

The lack of openness has been highlighted this week in The Times' investigation of two failed clinical trials in which patients died prematurely. In both experiments, The Hutch and its doctors had financial connections to some of the drugs being tested. Patients were not told of those ties, nor were they fully informed of the experiments' risks.

In one of the experiments, at least 20 patients died from causes attributable to their treatment; some of them would have likely lived a full life with conventional treatment. In the other, at least four died from their treatment.

The newspaper was led to one of these clinical trials by a doctor who had been on the inside as a member of a Hutch internal review board, and to the other by the son of a woman who died from treatment.

Whether other clinical trials at The Hutch - including those that are ongoing - have had similar issues is unknown. The Hutch operates in extraordinary secrecy - justified in the name of commercial confidentiality, grown from its maverick roots.

Dr. Howard Shulman, a pathologist in the clinical division at The Hutch, says he and others have questioned whether the center should have such close ties to companies. But Shulman said he was told by Dr. C. Dean Buckner, an original member of The Hutch: "We lost our virginity a long time ago."

Partnerships with business

Supporters say partnerships with business provide incentive, reward and seed money for innovative medical research. But numerous academic studies show that medical research may be impacted, at least subconsciously, by private financial incentives.

In a 1986 article in The New England Journal of Medicine, Dr. Richard Davidson analyzed reports on drug trials in five leading medical journals. He found that when drug companies sponsored the trials, researchers were significantly more likely to favor the drugs being tested.

Dr. Marcia Angell, editor of the prestigious journal, warned last year of "a Faustian bargain" when research centers "make available their precious resources of talent and prestige to carry out research that serves primarily the interests of the companies."

Angell asked, "How can they justify rigorous conflict-of-interest policies for individual researchers when their own ties are so extensive?"

The Hutch won't disclose financial connections of its research doctors or of the center itself. It won't say what stock it owns. It won't say what experiments it is performing for the companies whose stock it owns. It won't say what inventions and patents it is licensing to those companies, or for what prices.

To do so, Hutch President Dr. Lee Hartwell says, could violate confidentiality agreements with private companies.

Several clinical researchers at The Hutch who hold patents have written about their discoveries without disclosing their financial interest in print, a Times review of more than 1,000 medical journal articles has found.

Some journals require such disclosure, and Johns Hopkins University, among others, requires all of its researchers with financial interest to publicly disclose them.

The Hutch does have a policy regulating conflicts of interest, but that policy has been weakened over the years.

In 1983, during Protocol 126 - one of the experiments described in The Times earlier this week - the policy said no Hutch scientist could participate in any study or patient care in which he or she had any outside interest.

That policy was not enforced in the case of Protocol 126, as all three of the researchers had ties to a company that owned licensing rights to some of the drugs being tested.

Today, the policy says only the "principal" investigator must avoid financial holdings that can be affected by the experiment.

Appelbaum

Other researchers involved in studies and patient care can hold interests in private companies whose products they are testing as long as they report them to Dr. Fred Appelbaum, the director of clinical research. There is no limit on the amounts they may own - and no required disclosure to the subjects of their experiments.

Appelbaum says fewer than 10 percent of the clinical doctors at The Hutch have had conflicts. He says he has had to "manage" three or four situations. Citing privacy, he won't talk about details.

Some have stricter rules

The Hutch's current policy matches a 1994 guideline by the National Institutes of Health, and many research centers nationally have similarly loose restrictions.

But some major centers - among them Harvard University, Johns Hopkins University, UCLA, the University of Minnesota, the University of Kentucky, the University of Nebraska and even a Hutch partner, the University of Washington - are tougher.

To begin with, a few of them require research doctors to tell patients when they have private financial interests.

"It's the appropriate thing to do," said Steve Peckman, associate director for human-subjects research at UCLA. "If an investigator has an interest in the product or the company sponsoring the study, any reasonable subject would probably want that information."

A typical disclosure might say, "Dr. Smith received payment from Jones Company, sponsor of the study, for giving presentations."

Hartwell, Hutch president, says, "It's such a complicated issue that I'm not sure it makes sense to ask a patient to decide whether that's relevant or not. I don't think that's the way to handle it. I think the way to handle it is for the institution to be sure that no financial interest has an opportunity to have an influence on the outcome of the study."

The University of Washington Medical School, which works closely with The Hutch, doesn't give such information directly to patients. But unlike The Hutch, the UW does make its corporate sponsors, licensing deals and medical professors' reports of outside income available as public records, available on request.

Harvard Medical School flatly prohibits faculty from owning more than $20,000 in stock in companies whose products they are testing. Harvard reaffirmed the strict policy last year despite warnings it could lose some star faculty who wanted to make more money.

New York's renowned comprehensive cancer center, Memorial Sloan-Kettering, has far fewer spinoffs and potential conflicts of interest than The Hutch, despite having a faculty five times larger.

"Our board is very conservative," Senior Vice President James Quirk explained. "They're still concerned about what (private work) does to the faculty, meaning does it divert their attention from the work they do here."

While The Hutch has spawned more than a dozen private biotech companies, only one has spun out of Sloan-Kettering. Quirk said it was started because no vendor stepped forward to market a vaccine the hospital needed.

Sloan-Kettering requires all scientists to report potential or actual conflicts of interest internally. Quirk says only two scientists in 18 years have exceeded the limit of $10,000 or a 5 percent interest, and neither was in the clinical division, where human experiments are conducted.

Sloan-Kettering hasn't had institutional conflicts of interest with owning biotech stock, Quirk says, because it rarely asks for stock and always sells it fast.

"We feel it's cleaner," he said. "It's much easier for somebody who would ask you, `Do you have stock in that company?' We say, `Absolutely not.' "

Hartwell, meanwhile, says The Hutch should get more, not less, stock from biotech companies with which it is involved.

The Hutch sold $50 million in stock between July 1998 and July 1999, taking $3.6 million in profits, an IRS report shows. The center apparently acquired other stock and was left with about $40 million in corporate securities. It has repeatedly refused to discuss its stock dealings.

Rosetta Inpharmatics, a $250 million company co-founded by Hartwell and Dr. Stephen Friend, gave The Hutch 352,000 shares of stock for a licensing and research deal. Hartwell, hearing grumbles in the hall, gave The Hutch his own 283,200 founder's shares to avoid a personal conflict of interest.

The role of the review board

Hutchinson doctors today give two levels of scientific review to clinical trials and say they spend at least two hours with each prospective patient. But the primary safeguard against ethical and medical problems at The Hutch remains its Institutional Review Board.

The IRB, as it is known, is required by law for federal funding of any medical experiment involving humans.

Each month, two groups of about 10 people gather around tables in the E. Donnall Thomas Building on the Hutch campus.

Before each of the members is an imposing packet of papers stamped "confidential." The packets can't leave the room. They are carefully collected at the end of each meeting.

Inside are the details of 25 or so medical experiments on human beings. Five or six are new; the rest are ongoing.

The IRB's job is to ensure that subjects of medical experiments are treated in an ethical and humane manner, are fully informed, and that the potential benefits of the experiment outweigh the risks. It's a daunting task.

Waiting to speak to them are the center's most respected doctors - the ones who bring in millions of dollars in grants.

Down the hall is Dr. Thomas, a living legend who at 80 still works part time in an office in the building named in his honor.

The IRB members are all unpaid volunteers. The Hutch keeps their identities secret, but they include a housewife with a science background, a human-resources consultant, an attorney, a finance officer at a research institute and a risk-management expert. The others are doctors, nurses and pharmacists.

One former IRB chairman said the board was tough when going over patient informed-consent forms. For instance, "We made sure not to have polysyllabic words when a monosyllabic would do." But he refused to be quoted by name or to answer further questions unless, he said, The Times got a court order.

Center spokeswoman Susan Edmonds has for months refused to say who sits on the IRB. "We have nothing to hide," she said, asserting that members want to keep their identities secret to avoid being bothered by reporters' calls.

The Times did learn that two board members designated as "nonaffiliated community members" - which the federal government requires - were, in fact, being paid by The Hutch to perform legal work.

Suzanne Kelly Michael sat on the IRB from 1994 to 1998. Court records show Michael represented The Hutch in a major lawsuit in 1997 and 1998, while she was on the IRB.

Asked about that, Michael said that when she joined the board, she didn't personally work for The Hutch, though her firm, Lane Powell Spears Lubersky, did. The Hutch refuses to say how much Michael or the firm was paid during the time she sat on the IRB.

Paul Nordsletten replaced Michael in July 1998 as the "nonaffiliated" member. He works for The Hutch as an attorney on employment cases.

"At least in my own mind it's never made a difference because the two things are so different," he said, adding, "My work for them is sometimes very substantial and other times is not." Nordsletten lists The Hutch first among his clients in a lawyer directory.

After The Times raised questions about these lawyers' work as "nonaffiliated" members of the key review board, IRB administrator Karen Hansen said she asked all members of the IRB to study the statement of nonaffiliation and to report any problems. Hansen said the two lawyers then did so. She said some other people were "close" but not disqualified.

Helen McGough, IRB administrator for University of Washington research, where names of IRB members are public, said the UW "would not consider a person who has any financial relationship to be a nonaffiliated member." The purpose is to be "an outsider to the institution,'' she said.

At The Hutch, not only are the IRB's meetings closed, but also the meetings of the center's Board of Trustees. Although 68 percent of the center's funding - $140 million last year - comes from taxpayers, Hutch officials say they feel no legal or ethical obligation to open the meetings.

That attitude, and The Hutch's insulated approach, should be reassessed by its leaders, said Mary Faith Marshall, director of the program in bioethics at the University of Kansas Medical Center.

"I hope that approach will change," said Marshall, who is chairing the National Human Research Protections Advisory Committee, a blue-ribbon panel looking at such issues at research centers across the country.

"The model should be one of transparency. There should be no secrets."

Duff Wilson's phone number is 206-464-2288. His e-mail address is dwilson@seattletimes.com.

David Heath's phone number is 206-464-2136. His e-mail address is dheath@seattletimes.com.