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By Llewellyn Hinkes-Jones
Dec. 2 — Patients and researchers have harshly criticized the leniency of research misconduct findings against former Duke University cancer researcher Anil Potti and the sole focus on Potti by the Department of Health and Human Services Office of Research Integrity.
On Nov. 9, the ORI made a formal finding of research misconduct against Potti for altering data sets, falsifying grant applications and disregarding accepted scientific methodology surrounding his widely celebrated “Holy Grail” of cancer research. While Potti neither admits nor denies his guilt, the ORI banned Potti from U.S. Public Health Service-supported research for five years.
Potti's studies looked at the use of gene expression patterns to predict responses to therapy in lung and breast cancer patients.
In an editorial for The Cancer Letter, Keith Baggerly, a biostatistician at MD Anderson Comprehensive Cancer Center at the University of Texas, and C.K. Gunsalus, director of the National Center for Professional and Research Ethics, both called the ORI's penalty for research misconduct against Potti “too light.” They added, “neither justice nor the research community have been served by this outcome.” Baggerly originally discovered the potential misconduct along with Kevin Coombes, professor of biomedical informatics at Ohio State University.
Others voiced criticism as well:
Earlier this year, Potti and Duke settled two civil lawsuits brought by cancer patients who were treated by Potti. The lawsuits also claimed that numerous other Duke researchers and employees knew about Potti's flawed research, yet did nothing about it.
Duke has stood by the contention that it was Potti alone who was responsible for the research misconduct, but previously admitted that there were mistakes in overseeing Potti's work.
Doug Stokke, vice president of marketing and communications for Duke Medicine, applauded the result of the ORI investigation for “[absolving] the clinicians and researchers who were unwittingly associated with his actions.” Dr. Robert Califf, vice chancellor of clinical and translational research and director of the Duke Translational Medicine Institute, previously admitted that “there were numerous missed signals,” and ambiguity in the lines of authority and oversight. Califf is President Barack Obama's nominee to head the FDA.
An HHS representative wouldn't confirm or deny whether there would be additional ORI investigations. The ORI is limited in its investigative ability because it lacks subpoena power and relies on the institution where the misconduct took place to handle the investigation. But the agency can refer criminal behavior to the Office of the Attorney General in the Department of Justice for further prosecution.
Since Potti's clinical trials were finally suspended by Duke and his published papers in major medical journals were retracted, numerous questions have arisen about Duke's handling of the affair and lax approach to research oversight. Criticism of Potti's methods first started appearing almost immediately after Potti published his research and long before any action was taken by Duke. Dr. David Beer, an investigator with the National Cancer Institute (NCI), tried contacting Duke administrator Joseph Nevins about errors in Potti's data in 2006. Other NCI researchers found problems in 2007.
Both Baggerly and Coombes began looking at Potti's data in 2006 and eventually published a thorough criticism of Potti's research in Nature Medicine the next year. Both Baggerly and Coombes also tried communicating to Duke that such flawed data could result in patient harm or increased risk. According to Baggerly, Duke never formally responded to their concerns. He added that Duke administrators had dismissed their criticisms as arcane statistical issues, but the problems they highlighted were not complex. While it took Baggerly and Coombes many hours to completely delve into Potti's research, the errors in the data were readily visible. “The data was a mess. Rows were scrambled. Patient labels were wrong. Genes were wrong. Responders were wrong.”
Additionally, Duke continued to stand by Potti even after his misconduct was revealed and the scandal broke. Based on information discovered by the website Retraction Watch, Potti was given “glowing references … from the highest ranks of the Duke University School of Medicine and Duke University Medical Center” after he left the university. All told, the North Carolina Medical Board made 12 medical malpractice findings against Potti from 2008-2010.
According to The Cancer Letter, documents released in the civil trial revealed that issues with Potti’s data were known to numerous administrators within Duke, including his mentor and co-author Nevins. An e-mail from Holly Dressman, a researcher in Potti’s lab and co-author on a key paper to Nevins, called the data related to “topotecan signatures” in ovarian cancer “a big mess.” She questioned whether the results were real and worried that the NCI might ask them for the raw, error-riddled data.
Yet, according to a report by the Institute of Medicine (IOM), “none of the co-investigators in the series of publications from Duke raised concerns” . When an external review of their data was published in Lancet Oncology, both Nevins and Potti insisted that the data provided to the external reviewers were blinded—that the Duke researchers didn't have access to the data that their methodology was intended to predict. But co-authors on the review paper from the European Organisation for Research and Treatment of Cancer contradicted this claim and reported that the data were not provided blinded.
While the IOM report indicated that none of the co-investigators raised concerns about the data, information presented during the civil trial also revealed that one person did raise major concerns. Bradford Perez was a medical student in Potti's lab concerned about the reliability of the research he was working on. He addressed his concerns to Nevins, had his name removed from all publications, and kept his protestations quiet to all outside parties. No reference to a whistle-blower was included in the IOM report, yet the IOM report gave thorough recommendations about how to provide an environment safe for whistle-blowers to not allow such mistakes in the future.
While the IOM investigation wasn't intended as a study of the Duke scandal, it included a section on best practices for encouraging whistle-blowers. Jennifer Walsh, a representative for the IOM, added that the IOM doesn't usually comment beyond what is contained in its reports and that it stands by what was originally printed even if it didn't include pertinent information about the existence of a whistle-blower.
Eventually, the NCI formally stepped in to address the concerns about the data raised by Baggerly and Coombes, and met with Duke faculty in September 2009. Duke then temporarily suspended the clinical trials underway in October 2009. To validate Potti's and Nevins's research, Duke administrators Victor J. Dzau, M.D., chancellor for health affairs, and Sally Kornbluth, previously vice dean for Basic Science at Duke University School of Medicine, organized an external review to verify Baggerly's and Coombes's critiques. But according to Baggerly, the review was extremely flawed.
The reviewers were kept anonymous to everybody except Potti, Nevins and other Duke administrators, and remain anonymous to this day. While the majority of Baggerly's and Coombes's criticisms were over Potti's data, both Baggerly and the NCI believe that Dzau and Kornbluth wrongly tasked the reviewers with checking Potti's methodology rather than his data. Baggerly insisted that the majority of issues with Potti's work were with his data, not the methodology, and he clearly communicated this to Duke administrators.
Upset with the findings of the external review and the restart of the trials, the NCI then demanded the data from Duke to review for themselves. But before the NCI could completely review the problematic data, Potti's trials were cut short for reasons other than their scientific integrity.
According to Lisa McShane, chief biostatistician with the NCI during the review, Duke administrators assured the institute that they would look into the scientific underpinnings “to assess, analyze and comment on the specific issues cited by Baggerly and Coombes”—which the NCI took to mean both methodology and data. In the end, Nevins and Potti were also able to meet with the external reviewers and limit what information they were allowed to validate, and, according to a historical perspective document provided to the IOM, Baggerly's and Coombes’s criticism was never conveyed to the reviewers. In the end, the external reviewers confirmed that the items they were tasked with validating were accurate, but the information they provided was incomplete. And on Jan. 29, 2010, Duke announced that clinical trials would restart. Upset with the findings of the external review and the restart of the trials, the NCI then demanded the data from Duke to review for themselves. But before the NCI could completely review the problematic data, Potti's trials were cut short for reasons other than their scientific integrity.
On July 16, 2010, The Cancer Letter revealed that Potti falsified his background as a Rhodes Scholar. As a result, his research would be scrutinized, his trials halted and he would be put on administrative leave.
Originally, Potti struggled to find funding for his research, even after publishing his ground-breaking studies in Nature Medicine and the New England Journal of Medicine. H. Kim Lyerly, director of the Duke Comprehensive Cancer Center, complained about how stagnant National Institutes of Health (NIH) budgets threatened to derail Potti's research, and that Potti at that point was unable to obtain RO1 basic research grant funding from the agency.
In the civil trial, Duke researchers admitted that they were certain to obtain an enhanced reputation, earn money and get more “patients, students and professors from a ‘tag-on effect.' ” And Potti's success did just that. He would eventually earn two grants from the NIH worth more than $700,000, as well as grants from the American Cancer Society and others. His research was named the top science story of 2006 by Discover Magazine, both he and Nevins were crowned “Health Care Heroes” and Duke featured Potti in advertisements for the university's research department.
Their research was cited in major court decisions on intellectual property law and House testimony for NIH funding, and it also led to two separate patents for personalized cancer treatments and predicting responsiveness to cancer therapeutics. More than a hundred cancer patients signed up for clinical trials based on the rousing success. Many parties involved stood to profit handsomely from Potti's research. Using Duke's projections, The Cancer Letter estimated that Potti's license on a biomarker for ovarian cancer alone would be worth $2.1 billion a year.
In January 2007, Nevins, Potti and fellow Duke researcher Dr. Geoffrey Ginsburg formed Oncogenomics to capitalize on the gains they might reap from licensing their intellectual property for cancer biomarkers, which wasn't disclosed as a potential conflict of interest during their research. Oncogenomics would eventually change its name to CancerGuideDx, and enter into licensing agreements with Duke and Laboratory Corporation of America (Labcorp) months before the scandal broke.
Both Califf and Dzau, who both testified during the Potti civil lawsuits, have also been previously accused of conflicts of interest with industry. The Duke Chronicle noted that Califf earned thousands of dollars for consulting fees from pharmaceutical companies. Colleagues defended his connections as being a result of the nature of current-day research funding, which largely comes from private industry. Dzau is on the board of various private companies such as Alnylam Pharmaceuticals Inc., PepsiCo Inc. and Medtronic, while earning more than $2.2 million a year in 2009 from the university, with a base salary of $979,000. Dzau is also the president of the IOM, which did the academic review of the Potti case.
Potti's research at the intersection of biomarkers, personalized medicine and cancer therapeutics was where Duke was heavily investing at the same time Potti was reaping research success and publicity. From 2007 to 2010, Duke signed numerous agreements for large-scale research projects with Labcorp and David Murdock, the owner of Dole Food Co., at the Duke campus and at the recently built North Carolina Research Campus (NCRC) in Kannapolis, N.C., at the site of a former mill owned by Murdock. Both Dzau and Califf are on the board of the David H. Murdock Research Institute along with then-chief scientific officer for Labcorp, Andrew Conrad.
In 2007, Duke announced the establishment of the Measurement to Understand Reclassification of Disease Cabarrus/Kannapolis, or MURDOCK, study, with a $35 million grant from David Murdock to collect biological samples from citizens of the town of Kannapolis. All of it aimed at researching disease biomarkers. In 2008, Duke announced an agreement with Labcorp to develop a biorepository to hold biological samples from the MURDOCK study. And in the same year, the two organizations announced the development of a “biomarker factory”—a private collaboration to develop and market the intellectual property for biomarker-based laboratory developed tests. And in 2009, Duke broke ground on its new $400 million Duke Cancer Center, which was spearheaded by Dzau. In 2010, Duke also announced its personalized medicine initiative headed by Dzau and Ginsburg, in collaboration with Labcorp. Victoria Christian, chief operating officer with the Duke Translational Research Institute, who was instrumental in both the MURDOCK study and the biomarker factory agreements, insisted that nobody from the Potti or Nevins labs was involved with the agreements, but she declined to comment on whether Potti's publicity helped (although Dzau, who helped announce both initiatives, was involved in the flawed external review of Potti's work).
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