An update on The Hutch: Issues raised in last year's series about respected cancer research center continue to reverberate
Ten months after the Fred Hutchinson Cancer Research Center found itself the subject of a newspaper investigative report, its leaders and lawyers work to defend the acclaimed institution in a court of law and in the court of public opinion.
While the center insists there were no improprieties in two controversial clinical trials, it is closely considering reforms that would address some of the key issues raised in last March's stories in The Seattle Times.
That series, "Uninformed Consent: What patients at 'The Hutch' weren't told about the experiments in which they died," reported on two clinical trials in which patients were not properly informed of the risks of their treatments, nor of the financial interests of the center and its doctors in the drugs being tested.
At least 20 patients died prematurely in the failed experiments, of causes directly attributable to their treatment.
While the series brought angry rebuttals from Hutch officials, it inspired those working for reforms in the rules that govern human medical experimentation. It provoked the center itself to begin a process that may bring major policy changes. And it spurred a new federal investigation and lawsuits against The Hutch by seven survivors of patients who died in the two experiments.
Here, in question-and-answer form, is an update on what's happening:
REFORM AT THE HUTCH
Q: Shortly after the stories were published, the Hutchinson Board of Trustees put together a citizens committee to study the center's policies and procedures. What became of that?
A: The Committee for Patient Protection in Research Trials hired four consultants, met over five months and issued its report to the board Sept. 7. The committee, chaired by the Rev. William Sullivan, former president of Seattle University, was then disbanded.
Q: What did the committee find? What did it recommend?
A: The committee looked only at current practices, and not at the experiments described in The Times' series. While finding that The Hutch was complying with current rules, the committee recommended "an outright prohibition" on all financial interests in clinical trials by doctors, nurses, other staff and their immediate families. That would give the center the toughest conflict-of-interest policy in the nation.
The Hutch itself would be allowed to have financial interests in trials, but such holdings would have to be disclosed to patients.
The committee also recommended: hiring two new staff people and a bioethicist to help the internal review board that assesses the safety and ethics of proposed experiments; setting up better systems to report unexpected deaths; establishing an independent Data Safety Monitoring Board; and taking national leadership on informed-consent and financial-conflict issues.
Q: What happens from here?
A: The Board of Trustees appointed a new standing body called the Patient Protection Oversight Committee, composed of eight trustees, including Sullivan. They are charged with evaluating and implementing the reform recommendations.
Attorney Bruce Pym, chairman of the committee, says they are just getting started but are "pushing ahead."
Q: Why is this process taking so long?
A: Pym says thoroughness is more important than speed, and some officials are concerned The Hutch might lose some staff if it adopts tough new conflict-of-interest rules that preclude having financial interests in research.
Q: Haven't the ethics of clinical trials been an issue across the country, and not just at The Hutch?
A: Yes. Research centers including Harvard and Johns Hopkins universities are debating whether patients are adequately informed of risks. Medical researchers also are debating whether financial entanglements are tainting their research and damaging their credibility.
Dr. Marcia Angell, a former editor of The New England Journal of Medicine and a leading advocate for reform, has called for an outright ban on financial interests.
Q: What prompted this debate?
A: It took off with the death of 18-year-old Jesse Gelsinger in a gene-therapy experiment at the University of Pennsylvania in 1999. An investigation of Gelsinger's death uncovered evidence the experiment was unsafe. And unknown to Gelsinger's family, the lead researcher, Dr. James Wilson, owned 30 percent of the company whose substance was being tested. Wilson reportedly made $13.5 million from the sale of that company.
The Times' stories about The Hutch propelled the discussion, and it intensified last June with the death of a healthy volunteer in an asthma-drug experiment at Johns Hopkins in Baltimore.
Q: What's happening on the reform front nationally?
A: A lot of talk, but so far, little action.
The federal watchdog agency, the Office for Human Research Protections, last year moved to a higher level directly under the secretary of the Department of Health and Human Services. Its new director, Harvard anesthesiologist Dr. Greg Koski, is focused more on education than on discipline.
Another group, the National Human Research Protections Advisory Committee, has been meeting for 13 months and is advising the Bush administration. That panel next meets Jan. 28-29. In addition, the General Accounting Office, which is Congress' watchdog agency, and the Association of American Medical Colleges recently wrote reports on financial conflicts of interest in research.
Q: What's happening in Congress?
A: U.S. Senate hearings on human-research reform are scheduled March 19. Among those seeking to testify are family members of some patients who died in the Hutchinson Center experiments.
Sen. Edward Kennedy, D-Mass., and Sen. William Frist, R-Tenn. — the ranking members of the subcommittee on public health — were on the verge of introducing reform bills before Sept. 11.
"Unfortunately, the events of Sept. 11 had a significant impact on the Senate's ability to deal with the clinical-trials legislation," said Kennedy spokesman Jim Manley. "This is an important part of Kennedy's health-care agenda."
U.S. Reps. Diana DeGette, D-Colo., and James Greenwood, R-Pa., are crafting similar legislation in the House.
Q: Are government officials investigating the Hutchinson cases?
A: The Office for Human Research Protections opened an investigation in March. It still is open, and the office declines to comment.
THE HUTCH LAWSUITS
Q: Survivors of some of the patients have filed suits against The Hutch and its doctors, haven't they? Who are those people and what are their claims?
A: Six people have filed suits in connection with Protocol 126, a blood-cancer experiment conducted from 1981 to 1993. In that experiment, substances called monoclonal antibodies were used to deplete certain blood cells, called T-cells, in donated bone marrow before it was transplanted into cancer patients. The goal was to reduce a complication called graft-versus-host disease, but the researchers ultimately found that T-cells were necessary for successful transplantation.
The plaintiffs are: Cullen Couch of Charlottesville, Va., a marketer for LEXIS Publishing; Joe Fisher of Los Gatos, Calif., a salesman for Hitachi Instruments; Peggy Draheim of Scottsdale, Ariz., a homemaker; Annmarie Almedia Ridings of Mattapoisett, Mass., a social worker; Pete Wright of Heflin, Ala., a drugstore owner; and Cheryl Chambers of Richmond, Va., a high-school teacher.
All say they and their deceased family members weren't properly warned of the risks and alternatives to the experimental treatment, nor of possible conflicts of interest. They say Protocol 126 violated federal and state laws and the Nuremberg Code requiring the voluntary consent of human subjects.
Five other families are preparing lawsuits, according to their lawyers.
The lawyers believe that most of the more than 82 families in Protocol 126 have not yet heard about the reported problems in the experiment. The plaintiffs' attorneys plan to ask The Hutch to notify those families, but The Hutch has previously declined to do so, citing privacy.
One lawsuit has been filed in connection with the other experiment on which The Times reported: Protocol 681, a breast-cancer trial conducted from 1991 to 1998. In that experiment, featuring extraordinarily high doses of chemotherapy, Allan Berman of Spokane, whose wife, Kathryn Hamilton, died in 1993, is suing The Hutch for promising her a "rescue drug" the center didn't have.
Q: What does The Hutch say in response to these suits?
A: The Hutch says its doctors gave complete information to all patients to obtain their fully informed consent to enroll in these experimental treatments.
Q: Are the Protocol 126 plaintiffs' cases being bundled into one, or are they being handled separately?
A: Separately. U.S. District Judge Robert Lasnik in Seattle has denied a motion for class certification, saying each case was unique. However, attorneys for the families plan to argue that the cases should be tried before the same jury.
Q: What is the status of those cases?
The Protocol 681 case is scheduled for trial Sept. 16. The Protocol 126 cases are a year or more away from trial. Attorneys report no productive settlement talks.
THE HUTCH AND THE TIMES
Q: Recently, on its Web site at www.fhcrc.org, The Hutch posted assertions it claims proves The Times' stories on Protocol 126 are "false and unsupportable." What does the newspaper say to that?
A: The center repeated that position in a letter faxed to The Times Friday, after being notified of this article. In it, a Hutch official asks that The Times "stop repeating the false assertion that the Fred Hutchinson Cancer Research Center and its physicians stood to profit" from the clinical trials.
Times Executive Editor Michael Fancher says the newspaper stands by the accuracy and fairness of its stories.
In fact, the assertions by The Hutch are themselves misleading. Let's consider them one by one.
Q: OK. First, Hutch officials say The Times reported that the three doctors running Protocol 126 were more concerned with financial gain than with patient welfare, and The Hutch disputes that.
A: The stories never said that.
The newspaper was careful never to presume to know the actual motivation of the researchers. Only they know what drove them, and The Times quoted one of them as saying money was not a motivation in Protocol 126.
The newspaper did say the doctors had financial interests in their research: All three held stock and consulting positions with Genetic Systems, which held licenses to three of the drugs being tested.
Q: But The Hutch flatly denies that researchers in Protocol 126 had a financial conflict of interest.
A: The documented record and some experts say otherwise. The three principal researchers — Drs. John Hansen, E. Donnall Thomas and Paul Martin — received stock from Genetic Systems that would now be worth tens of millions. In addition to working at The Hutch, Hansen was medical director of Genetic Systems, Thomas was an advisory-board member of the company and Martin was a company consultant.
Shortly after the stock was given to the researchers, The Hutch sold exclusive rights to 37 of its monoclonal antibodies to Genetic Systems. Those antibodies were the company's chief assets. Three of those were being tested in Protocol 126 by the three researchers who'd been given the stock.
In fact, in 1984, Dr. Robert Day, then Hutch president, wrote that "conflicts of interest do exist for members of the scientific staff" with regard to Genetic Systems. And in a 1993 letter to a federal investigator, he referred to "conflicts of interest including the conflicts of Dr. Hansen and Dr. Martin."
As reported in the original series, Kamal Mittal, a federal investigator, said the researchers had violated The Hutch's own conflict-of-interest policy. And Dr. Robert Miller of the Washington Medical Quality Assurance Commission said, "To me, what (they) did was a clear conflict of interest. I think that's a pretty obvious, well-known ethical principle."
In response to The Times' series, The Hutch said last spring:
"According to today's policy, this would be a conflict of interest. However, in 1983 the Center was just beginning to understand these issues and develop policies. We have no reason to believe there was a conflict of interest, because Genetic Systems was not directly or indirectly involved in any marrow transplant studies. In addition, neither Dr. Hansen, Dr. Martin, the Hutchinson Center nor Genetic Systems has a patent for using monoclonal antibodies in marrow transplantation."
Q: So The Hutch asserts that the doctors could not have profited because they didn't hold the patent to the drug compounds. What about that?
A: First, it ignores the profit that the doctors could, and did, make on their Genetic Systems stock.
On the matter of patents: Ortho Pharmaceuticals was later awarded patents on some of the antibodies, but did not have them when Genetic Systems gave stock to the Hutch researchers or when Protocol 126 began. In fact, The Hutch sold licensing rights to the antibodies to Genetic Systems.
Further, some patent experts say that even with the Ortho patents, the Hutch researchers could have applied for what is known as a "use" or "method" patent, possibly giving them rights to a specific treatment using the antibodies. It also might have been possible for the researchers to have worked out a deal with Ortho to pay royalties.
Even Dr. Gideon Goldstein, the Ortho scientist who holds the patents to the Ortho materials, says the scope of his patent rights likely would have had to be decided in court had another party applied for a patent. Asked whether The Hutch could have made money off its antibodies, he said, "That would be up to court."
Notably, Goldstein says he offered his clinical-grade antibodies to The Hutch for testing at the start of Protocol 126 but his offer was declined by Hansen.
"I guess it's competition," Goldstein said. "Everybody has their own fish to fry."
Another scientist at that meeting confirmed Goldstein's account.
Q: The Hutch also says the researchers publicly disclosed their work with monoclonal antibodies and T-cell depletion in a medical journal in 1981, and in doing so foreclosed any possibility of commercializing the fruits of their research. Is that true?
A: No. Expert patent lawyers say the 1981 article did not preclude the possibility of patenting and profiting from the new method if it had succeeded.
The article describes how to make three monoclonal antibodies and speculates that anti-T-cell drugs might prove useful in preventing graft-versus-host disease.
Protocol 126 tried several different methods with the antibodies and ultimately failed. Experts say it would have been a medical "home run" if it had succeeded, opening bone-marrow transplants to thousands more cancer patients.
Mark Janis, biotech patent expert at the University of Iowa College of Law, said a prior publication that speculates about using materials to achieve a result doesn't bar a later patent claim unless it discloses the specific steps of the method or contains sufficient teachings to suggest the method to a person of ordinary skill in biotech.
"If a publication discloses a rocket ship and speculates that the rocket ship might be used to take people to Saturn, but doesn't teach how that would be done, that publication doesn't necessarily preclude a later inventor from patenting a specific method for using the rocket to get to Saturn," he said.
Lawrence Sung, biotech patent expert at the University of Maryland School of Law, said early research failures would tend to show that a later success was the result of "a nonobvious idea," and thus patentable.
After reviewing the 1981 article, Sung said the specific antibodies it described would not be patentable if the inventors had not sought patent protection within one year after the date of publication, but "the methods of using them to prevent graft-versus-host disease might be patentable if they represented a new, nonobvious use or other significant improvement."
"Certainly it is possible to have materials in hand and find a method for using them which would be separately patentable," Sung said.
Toshiko Takenaka, director of the Center for Advanced Study and Research on Intellectual Property at the University of Washington School of Law, agreed, noting that "U.S. patent law requires specificity."
Finally, The Hutch, in 18 years of questioning by review-board doctors, federal and state investigators and Times reporters about conflict of interest, never until recently claimed that this 1981 article would foreclose the possibility of patents. In fact, the '81 article was never even mentioned in later medical-journal articles on Protocol 126.
The 1981 article could have, arguably, started the clock on a specific window of patent opportunity, a opportunity the researchers bypassed. That might support their assertion that they were not motivated by money. At that time, however, the experiment was proving difficult and unsuccessful.
Hansen has conceded on several occasions that the situation — being involved in a company that dealt in monoclonal antibodies and at the same time conducting experiments on patients with monoclonal antibodies — was less than ideal.
"If I could do anything to reconstruct what happened 20 years ago, understanding the issues of perception, I would have removed myself completely from those clinical trials," he said last March.
Q: Is it true, as The Hutch says, that Genetic Systems was "not even aware of the T-cell depletion trials and had no interest in their results"?
A: No. Minutes of a Feb. 12, 1981, special meeting of the center's Human Subjects Review Committee show that Dr. Robert Nowinski — a former Hutch scientist who was co-founder and executive vice president of Genetic Systems — attended and urged the committee to approve Protocol 126.
The month before that meeting, Nowinski gave penny-a-share stock and positions to the three principal researchers on Protocol 126. On the meeting date, the stock was worth at least 60 cents a share, or $600,000 to Nowinski, $150,000 to Hansen, $60,000 to Thomas and $6,000 to Martin. The stock was not revealed to the review committee.
A month later, Nowinski bought commercial rights to at least three of the antibodies to be tested in Protocol 126.
In Genetic Systems' investor prospectuses and its Securities and Exchange Commission filings, the company made broad claims of its interest in blood-cell antibodies, leukemia and cancer therapy, and noted its Hutch connections.
In its first quarter of being offered to the public, the stock skyrocketed in value. And 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 and Martin's to $105,000. Bristol-Myers stock has risen tenfold since then.
Q: The Times said Protocol 126 proposed experimenting with the healthiest patients first, rather than the sickest patients. The Hutch says this is "backwards." Who's right?
A: The Times' series was correct. Most of the patients in the early stages of the trial stood about a 50 percent chance of a cure with conventional bone-marrow treatment. In the later stages, patients had more severe cancers, with cure rates of 10-20 percent. In fact, the selection criteria were changed in May 1984 to exclude the healthier patients.
Q: On the specific case of Rebecca Wright, who was featured in the first article: The Hutch says she was told everything that was known about risks at the time she was enrolled in Protocol 126, in June 1985. Is that right?
A: Rebecca Wright's consent forms, as well as notes from her consent conference with Dr. C. Dean Buckner, document that she was not told what doctors knew or should have known, and was encouraged to enroll in the experiment.
For example, the consent form said vaguely, "graft rejection has occurred following such treatment." In fact, it was occurring more than 20 percent of the time in this experiment, compared with 1 percent in conventional bone-marrow transplants.
The Hutch says Wright was the first patient in a new arm of the study. She was told just one patient had died of graft failure in the previous arm. In fact, a second patient had died with no sign of engraftment 20 days after transplant but wasn't counted as a failure because he didn't survive the required 21 days. A third patient had only "very minimal engraftment" on her 57th day after the procedure — the day before Wright checked in.
Further, doctors were already noticing a higher rate of cancer relapse, but didn't tell Wright. The first 20 patients had seven relapses; the next 11 had five relapses; and a similar study showed 40 percent relapses compared with a control group's 5 percent.
Finally, the consent form and the conference suggested to Wright and others that should a graft failure occur, she would receive a second transplant. She was not told that all such second transplants done in the experiment had ended in death.
Wright's widower, Pete, says they would not have consented to Protocol 126 if they'd known all the facts.
Q: Dr. John Pesando, a former Hutch doctor, was cited as the whistle-blower in the articles. But Hutch officials say there is no record that he objected to Protocol 126 while he was at The Hutch. Which version is true?
A: The center's records of Institutional Review Board meetings for the mid-1980s are sketchy and don't show Pesando raising objections and questions. However, Pesando's notes from those meetings reflect his objections. Further, the chairman and other board members confirm Pesando's account that he was the leading voice questioning the experiment and the researchers' conflicts of interest.
In part at Pesando's urging, the board chairman at that time, Dr. Henry Kaplan, wrote to the center president urging more scrutiny of the experiment. In an interview with The Times, Kaplan recalled, "John (Pesando) was absolutely convinced there was a problem."
Pesando's actions since leaving the center — a 10-year crusade to get an investigation of the clinical trial — speak for themselves.