Federal investigators have accused a Canadian hospital of providing an American breast cancer study fraudulent data, including a falsified laboratory test result that may have endangered the health of a volunteer in the study.
The alleged fraud, which occurred at St. Mary’s Hospital Center in Montreal, concerns falsifications in the Breast Cancer Prevention Trial, a massive ongoing study intended to show whether the drug tamoxifen can reduce the incidence of breast cancer in women at increased risk for the disease.
The tamoxifen trial, which currently includes some 11,000 women in this country and Canada, is funded by the U.S. National Cancer Institute and administered by the University of Pittsburgh’s National Surgical Adjuvant Breast and Bowel Project. The project, known as NSABP, is the same organization that ran the landmark study purporting to show that lumpectomy is as safe as mastectomy in treating early breast cancers.
The falsifications, which affected data for only three of 47 patients enrolled by the hospital in the tamoxifen trial, were detected before they could influence the outcome of the study, which is continuing.
But it was the NCI’s discovery, in March 1994, that NSABP officials had remained silent for months about possible fraud at St. Mary’s that precipitated the removal of the NSABP’s longtime chairman, Dr. Bernard Fisher.
The NSABP first learned of discrepancies in the St. Mary’s data in September 1993, a few months after Dr. Roger Poisson, former chief breast surgeon at another Montreal hospital, admitted falsifying research data for nearly 100 subjects he had enrolled in other NSABP studies.
One of those accused in the tamoxifen case, a former St. Mary’s data manager named Barbara Jones, has accepted the finding by the Office of Research Integrity that she committed scientific misconduct. Jones’ successor, Catherine Kerr, has denied responsibility for any falsifications and is appealing the misconduct finding before the U.S. Department of Health and Human Services.
Kerr referred questions to her attorney, Richard McConomy, who asserted his client’s innocence. “What you’re talking about here is a secretary,” McConomy said. “The thing nobody here can understand is how we end up dealing with two secretaries, people at the lowest of levels, with the implication that there was no responsibility at the other levels.”
The ORI investigative reports for Kerr and Jones, partially censored copies of which were released under the Freedom of Information Act, maintain that the falsifications of which the two women are accused made it appear test results were normal when they were abnormal, or that tests had been performed as required when they had not.
Because the tamoxifen study is still in progress, no results or conclusions about the drug’s usefulness have yet been reported. The ORI said the falsified data had been expunged from the study’s computer database and would not appear in future reports.
The most serious of the falsifications, which the ORI attributed to Kerr, involved the changing of an abnormally high result for a blood test known as serum creatinine, which measures kidney function, to a reading within the normal range.
The abnormal reading would have made the subject ineligible for the study, in which women are randomly chosen to receive either tamoxifen or a placebo over a five-year period.
Investigators subsequently discovered a notation in the woman’s medical chart that she suffered from chronic renal, or kidney, failure.
“The result of the false information,” the ORI said, “was that a woman who had chronic renal failure which might have affected her response to the study drug was entered on the study. Entry on the study could have been detrimental to her health and safety.”
Asked how the woman might have been endangered, the ORI’s chief investigator, Dr. Dorothy Macfarlane, noted that tamoxifen is excreted through the kidneys.
“If the kidneys are not functioning optimally, the drug may build up to a higher level in the blood than in a person for whom the kidneys are working properly,” Macfarlane said. “The higher the dose, the more likely adverse reactions of any type.”
Although its proponents believe tamoxifen is capable of suppressing some breast tumors whose growth is enhanced by the hormone estrogen, studies have also linked the drug to elevated rates of uterine and liver cancers.
Macfarlane said ORI had not determined whether the woman whose lab data was changed had received tamoxifen or a placebo, because “we didn’t think it mattered. She never should have been entered on this study in the first place.”
In addition to falsifying the serum creatinine test result, Kerr is accused of having changed the date on the same woman’s four-year-old mammogram and her six-month-old electrocardiogram to make them appear current, and of having fabricated a normal blood calcium test result for a second subject whose blood had never been tested.
Because the trial is intended to show whether tamoxifen can prevent breast cancer in some women, the mammograms were necessary to establish that all participants were cancer free at the time of enrollment.
The study is also intended to see whether the drug can lower the rate of heart disease and osteoporosis. The electrocardiograms and blood calcium tests were necessary to detect evidence of pre-existing heart or bone disease.
Misrepresenting the electrocardiogram as having been performed six months later than it actually was, the ORI said, meant that any heart disease which might have occurred in the intervening period could have erroneously been attributed to the effects of tamoxifen.
“Important pieces of research data were fabricated and falsified by Ms. Kerr,” the ORI said. “The falsely reported data could have possibly skewed the outcomes of the study by giving the false impression that the women were healthy before they entered the (Breast Cancer Prevention Trial), or that no effects had been seen at the screening intervals required by the study.”
Kerr, a social worker by training whose principal position was that of administrative assistant in the hospital’s department of surgery, denied having falsely reported any data or altering any documents, although she acknowledged that she was the only person responsible for screening participants in the tamoxifen trial.
But the ORI concluded it was “not plausible that these alterations and false reports were made by anyone other than her, as no one else would have both access to the records and the motive to make it appear that the participants entered met the protocol requirements.”
St. Mary’s has received more than $26,000 in U.S. cancer research funds for its participation in the tamoxifen trial, or about $500 for each of the 47 women it entered.
The ORI said Kerr, who was brought in as data manager after Jones had recruited only 11 women in 12 months, was paid $250 for each subject she enrolled in addition to her secretarial salary and was under pressure “to accomplish more than her predecessor had been able to accomplish.”
Jones, who is no longer employed by St. Mary’s, was accused by ORI of having changed the date on a six-month-old report of a mammogram and breast exam for one of the subjects for whom Kerr allegedly falsified test results, and of fabricating the date of an electro- cardiogram for a third volunteer.
Jones acknowledged that a worksheet containing both the true and false dates of the mammogram and breast exam was in her handwriting, but told investigators she could not remember why she had written the note.
The ORI said it did not find her story credible, asserting that Jones “knew that the subject would be found ineligible for randomization if she reported the correct date of the mammogram and breast examination to the NSABP.”
“Although Ms. Jones denies falsely reporting any dates or data or having made any of the changes to documents,” the ORI said, “it is not plausible that these alterations and false reports were made by anyone other than her, as no one else would have both access to the records and the motive to make it appear that the participants entered met the protocol requirements.”
The first indication of trouble at St. Mary’s came during a routine NSABP audit in September 1993, when an auditor noticed that the date on a mammogram report was in a different typeface than the rest of the report. Moreover, the document gave the woman’s age as 68, although she had been born in 1919, 74 years earlier.
According to a National Cancer Institute memo obtained by the Tribune, the auditor told NCI investigators that he informed the NSABP’s then-chief statistician, Carol Redmond, immediately after returning from Montreal of what he considered “a serious problem” at St. Mary’s, and that he believed Redmond had told Fisher “shortly thereafter.”
Federal regulations require that the NCI be notified immediately of possible data discrepancies in any of its clinical trials. At the time of the St. Mary’s audit, the NSABP already had been privately reprimanded by NCI and ORI for having delayed reporting evidence of data alterations by Poisson for more than eight months.
Although the auditor recommended a return visit to St. Mary’s, the NSABP said-and did-nothing about the matter for nearly six months. The audit report, which under federal guidelines was supposed to have been forwarded to NCI, remained in the NSABP’s files.
In the wake of public revelations about the Poisson case, senior NCI officials were astonished to discover that no audit reports at all had been forthcoming from Pittsburgh for nearly eight months.
Asserting that they had “lost confidence” in Fisher’s leadership of the NSABP, the NCI sent its own auditors to Pittsburgh to review copies of all delinquent reports from the tamoxifen trial.
The 38 reports reflected what another NCI memo termed “a high frequency of unconfirmed data” at a number of hospitals, including New York’s Memorial-Sloan Kettering Cancer Center and the Dana Farber Cancer Center in Boston.
When the NCI auditors saw the six-month-old St. Mary’s audit, cancer institute investigators were dispatched to Montreal, where they sequestered NSABP research files and medical charts for the woman whose mammogram appeared to have been altered.
The chart contained records of the woman’s previous mammograms but none taken on Jan. 28, 1993, the date of the apparently altered mammogram report. A 1988 mammogram report in the woman’s file was an exact match for the purported 1993 report, as was another mammogram report attached to the subject’s medical chart that bore no date.
The ORI concluded that the alteration of the first report had taken place after Kerr learned the NSABP was planning to audit St. Mary’s, at which time she “would have been required to produce a mammogram report to document what had been reported” on the subject’s entry and eligibility form.
The removal of the date from the second copy of the 1988 report, the ORI conjectured, occurred shortly before the arrival of the NCI investigators, when Kerr-unaware that the NSABP auditors had photocopied the report with the altered date-substituted another copy of the 1988 report from which the date had been completely removed.
Beyond the apparent fraud, the NCI was concerned about whether the altered mammogram report had prevented the woman, who had had a mass in her right breast since 1984, from receiving appropriate medical care.
The radiologist who evaluated the woman’s 1992 mammogram, the most recent before her enrollment in the tamoxifen trial, concluded that the lump had increased in size and suggested that it be biopsied to see whether it was cancerous.
No biopsy was performed. When the NCI asked St. Mary’s whether “reports of possible abnormalities might have been ignored as a result” of the altered report, the hospital replied that, in the opinion of another Montreal surgeon, the radiologist had “over-interpreted” the seriousness of woman’s condition.
Coming less than three weeks after the first news reports of the Poisson affair, the NCI’s discovery that the NSABP had remained silent about the problems at St. Mary’s catalyzed the NCI’s frustration with Fisher’s leadership and administration of the NSABP.
“Even after NSABP discovered Dr. Roger Poisson’s scientific misconduct at Saint Luc Hospital in Montreal,” the NCI admonished University of Pittsburgh administrators in a letter, “mismanagement problems and lack of judgment continue to occur.” At the top of the NCI’s list of concerns was St. Mary’s.
Fisher, who recently assumed the post of scientific director of the NSABP, maintained he had not been informed of the problem at St. Mary’s until one day before the NCI investigators arrived in Pittsburgh. Redmond, who was replaced last week as head of the NSABP biostatistical center, did not respond to a fax letter asking when she had advised Fisher of the discrepancy at St. Mary’s.
The ORI’s Macfarlane said her agency had not investigated the reasons for the NSABP’s delay in informing NCI because “we have not been asked to rule on that.” Fisher and Redmond are the subjects of a separate ORI investigation into whether they knew certain data had been falsified by Poisson at the time they submitted it to medical journals for publication.
Last month, the U.S. Justice Department sued St. Luc’s Hospital for $518,000 in an attempt to recover federal funds paid to St. Luc to support the enrollment of subjects who later had to be expunged from NSABP studies because of Poisson’s falsifications.
Officials said that no decision had yet been made on whether to seek a similar rebate from St. Mary’s.
The NCI has agreed to allow St. Mary’s to continue its participation in the tamoxifen trial pending approval of a corrective action plan that would provide tigheter control and supervision on data collection.
