GREAT EXPENSE: Pittsburgh’s Bernard Fisher says that the government’s misconduct investigation against him cost too much.
Fisher, cleared earlier this month of any wrongdoing, has filed a lawsuit against the National Institutes of Health, the National Cancer Institute (NCI), the Office of Research Integrity (ORI), and the University of Pittsburgh. In his suit, he alleges his First Amendment rights were breached in the handling of the investigation and that he was denied due process under the law. He also contends that patients had to deal with undue concerns raised by an inaccurate portrayal of scientific research by legislators and the media. He wants to "make sure this doesn't happen again" to other scientists.
OUTSIDE INFLUENCE: Yale’s Vincent DeVita suggest that an independent agency, perhaps an IOM panel, oversee misconduct cases.
Fisher, 78, Distinguished Service Professor at the University of Pittsburgh School of Medicine, is the former director of the National Surgical Adjuvant Breast and Bowel Project (NSABP), an international, multi-trial undertaking sponsored by NCI. He had been in charge of the project since 1967. One study, which involved more than 480 sites, focused on a breast-sparing surgery called lumpectomy. It showed that the procedure, when combined with radiation therapy, was just as effective in treating many women with early-stage breast cancer as totally removing the breast. Lumpectomy entails removing only the cancerous tumor and surrounding lump of breast tissue.
In 1991, Fisher first reported to NCI officials that surgeon Roger Poisson had enrolled 99 ineligible women in the NSABP breast cancer trial at St. Luc Hospital in Montreal. But it wasn't until 1994 that the Chicago Tribune (J. Crewdson, March 13, 1994, page 1) reported Poisson had falsified data. The article, entitled "Fraud in Breast Cancer Study; Doctor Lied on Data for Decade," was followed by congressional hearings on scientific misconduct by Rep. John D. Dingell (D-Mich.), then chairman of the House Energy and Commerce Committee's subcommittee on oversight and investigations. According to a New York Times report (L.K. Altman, March 15, 1994), Poisson signed an agreement with the Food and Drug Administration that acknowledged he had falsified results of other studies, but he maintained that he did no more than tell "white lies" that would not have changed the findings of the lumpectomy study.
Under the increased media and congressional pressure, NCI took official action. The institute removed Fisher as head of the project. NCI did this despite subsequent reanalysis of the data by both Fisher and NCI statisticians that showed the falsified information didn't change the study's original conclusions. The institute asked ORI to investigate potential misconduct by Fisher for knowingly using data on ineligible patients in publications and then not acting swiftly enough to publish a corrected analysis of the revised data. The ORI investigation lasted two years and nine months.
"Of course, I'm relieved about the ORI's decision," Fisher says. Still, he notes, "we have to be aware of these things [misconduct] because it affects all scientists."
The fallout from the 1994 Chicago Tribune report of fraud was immediate, initially causing a slowdown in the rate at which women entered breast cancer clinical trials, cancer specialists note. Many women questioned the integrity of researchers, trials, and their findings. They also wondered about lumpectomy as a treatment choice. Some physicians and others involved in clinical trials contend, however, that when people realized that the incident was an isolated one, public trust in science ultimately suffered little.
WORRIED AT FIRST: Penn’s Barbara Weber points out that women were initially very concerned when they heard about fraud allegations.
Weber believes it is inevitable that such high-profile cases affect the public's perception of research: "I think it does undermine public confidence in clinical trials." Some women are skeptical of getting involved in a clinical trial anyway, she points out. The notion of being a so-called guinea pig for some unknown treatment is hardly attractive. On the other hand, she notes that many patients are desperate for treatment, and are "willing to jump on the bandwagon" and take a chance on experimental drugs and treatments.
Vincent T. DeVita, director of the Yale Cancer Center who was NCI director from 1980 to 1988, acknowledges public confidence in research may have been slightly damaged, but contends that the case had only short-term effects. NCI chief of surgery Steven Rosenberg sees such cases as rare, and any damage to public confidence from the case as essentially an "overreaction to an isolated instance."
Shortly after the story broke in the Chicago Tribune and the investigation began, five other NSABP-sponsored trials were halted. The hiatus lasted from March to November. One controversial NSABP study examined tamoxifen as a breast cancer preventative. Tamoxifen is anti-estrogenic, and one of the theories behind breast cancer is that estrogen may contribute to the cancer development. Yet tamoxifen also has side effects, such as an increased risk of uterine cancer. When the trial resumed, patient enrollment subsequently slowed.
FEW EFFECTS: Women’s health advocate Cynthia Pearson doesn’t see long-term reduction in trial participation from the Fisher case.
Fisher argues that many of those involved in the investigation didn't understand how clinical trials are conducted, which contributed to an aura of mistrust. "Our own process [of data collection] was very tightly monitored from the NSABP," he says. "You have built-in safeguards in the process to make sure data collection is accurate." For example, he notes that such large studies are statistically designed to take into account a certain number of cases that do not meet some eligibility criteria.
Fisher agrees that the aspect of public mistrust in science "has come to play a role in my story." He contends that media coverage has contributed to a "very palpable" mistrust. Women were practically "told they should be concerned, despite the fact that we have had a clinical trial of more than 50,000 women and that the information, once reanalyzed, showed no difference in results," he says.
He acknowledges that if he were a woman who had read the press coverage of the case, he too would have been "mistrustful." According to Fisher, once the media found out about the problems in the project, women as well as breast cancer research suffered. He notes that "perhaps millions of dollars [spent on the ORI investigation, in addition to the cost of delays in other trials] were lost."
The Fisher case, many scientists say, points to the need for researchers to pay more attention to misconduct. Fisher argues that science polices itself, not only through the peer-review system, but also because scientific discoveries must be replicated. "The whole gestalt of science is confirmation [of findings]," Fisher explains. "If someone does a paper that is substantially wrong, sooner or later it will be found."
PERCEPTION: Penn’s John Glick is concerned that the public will remember only that Fisher was accused of misconduct.
SELF-CORRECTION: University of Chicago’s Samuel Hellman argues that science can police itself.
Some observers argue that government bureaucracy makes an ineffective science watchdog. Zora K. Brown, president of Washington, D.C.-based Cancer Awareness Program Services, which develops cancer education programs, argues that the case was handled poorly by ORI. She argues that ORI may not be the "best watchdog." Brown, a member of the National Cancer Advisory Board, a group outside NCI that advises the government, thinks there is too much government bureaucracy involved, and that an independent counsel needs to be appointed. It might consist of representatives of government, industry, science, and the public.
Others agree the process should be depoliticized. Yale's DeVita suggests that a group from the Institute of Medicine, for example, might serve such a purpose.
MAKE IT SO: Illinois’ C.K. Gunsalus points out that in many cases, science can be effective in policing itself.
She points to a recent case involving Francis Collins, director of the National Human Genome Research Institute and the Human Genome Project. In August 1996, Collins went to federal officials after he learned that a graduate student in his laboratory had fabricated data over a period of two years in several publications (Notebook, The Scientist, Nov. 11, 1996, page 30). Collins subsequently retracted five published research papers on leukemia. He also wrote 100 or so letters to leukemia genetics researchers who might have read the retracted work, making the incident as public as possible. Gunsalus says Collins "clearly struggled with how to handle the case morally, but decided what he ethically should do, and has been praised by most scientists."
Marcel C. LaFollette defends government intervention. LaFollette, a research professor of international science and technology policy at George Washington University, argues that ORI has shown it can handle complex investigations.
"If everything worked perfectly, you'd have a system that would preserve the autonomy of the scientist to pursue his science. The [policing] body would act only in the best public interest, served both by the best type of investigation and not damaging science in the process," LaFollette believes. "This became a dispute and controversy, both among scientists and in the press, when scientists reacted to the discussion of scientific fraud and establishing formal regulations in investigations. They said, 'Oh, if you do anything, you'll ruin science.' I think they [the federal government] have developed a system through ORI that is promising a fair investigation and due process."
ORI acting director Chris Pascal sees his agency's efforts in investigating allegations of fraud as "important" for science. He believes the ORI's role is more of a collaboration between government and grantees.
He contends that ORI's work actually may help the scientific community to become more cognizant of issues. "It's a benefit to have such issues looked at objectively outside the institution in order to have confidence in the scientific process," he says.
Pascal thinks ORI has taken a black eye. He contends that ORI is a useful place for those who have concerns about the conduct of science. "If people make allegations and voice serious concerns, to have some objective resolution is good for the scientific community. We feel that we have a role in the public's confidence in research."
Few scientists, however, seem to have much sympathy for ORI. Many, such as Yale's DeVita, see the Fisher case as an unfortunate incident that damaged the reputation of a "giant in the field." He credits Fisher and the NSABP lumpectomy trial as "probably more responsible than any other in changing the face of breast cancer treatment in this country."
The public's loose grasp of the facts concerns some as well. Referring to the final ORI ruling of no misconduct by Fisher, Penn's Glick says, "The public doesn't remember that. It just remembers that he was accused and investigated."
Though unfortunate, the Fisher case may have done some good in making scientists more aware "that these things can happen," comments Gunsalus. She notes that while "scandal leads to regulation," it will be some time before the scientific community ultimately decides just how it wants to deal with scientific misconduct.