After a five-year investigation, the HHS Office of Research Integrity announced that it has settled with former Duke University researcher Anil Potti.
Under the agreement published in the Federal Register Nov. 9, Potti admits no wrongdoing and agrees to be barred from research funded through Public Health Service for five years.
The report doesn’t address the subject of responsibility on the part of Duke, the institution that employed Potti and conducted three clinical trials based on his model for choosing cancer therapies.
“We are pleased with the finding of research misconduct by the federal Office of Research Integrity related to work done by Dr. Potti,” Duke officials said in a statement to the media. “We trust this will serve to fully absolve the clinicians and researchers who were unwittingly associated with his actions, and bring closure to others who were affected.”
The Cancer Letter invited Keith Baggerly, a biostatistician at MD Anderson Cancer Center, and CK Gunsalus, an expert in scientific misconduct at the University of Illinoisat Urbana-Champaign, to analyze the ORI action.
“This case is about as serious as one can imagine at the individual level. At the institutional level, it is beyond disappointing at every turn: in handing an internal whistleblower, in responding to credible, serious and repeated external scientific queries, in managing the multiple conflicts of interest in the situation, in limiting the information available to an interim scientific review, in how its leaders testified to an IOM review committee, in its legal responses,” Baggerly and Gunsalus wrote.
“A case with millions of taxpayer dollars misused, totally fabricated research, damage to hundreds of patients recruited for treatment with ‘the holy grail’ of cancer treatment, and a pathetic institutional response is being closed with a five-year funding ban for one investigator, individually and alone. “
Their guest editorial appears here.
Joyce Shoffner, a breast cancer survivor who was treated in one of the Duke trials that enrolled 117 patients, described the settlement as a “travesty.”
“The results are a slap in the face to patients who died and for the two patients that are still living the horror of those clinical trials,” Shoffner said to The Cancer Letter. “No slap in the face or even a tap on the wrist for Potti.”
Kevin Coombes, visiting professor at The Ohio State University College of Medicine Department of Biomedical Informatics, said he is disappointed by the conclusion of the case.
“ORI accepted a voluntary settlement agreement from Dr. Potii in which he ‘neither admits nor denies ORI’s findings of research misconduct,’” said Coombes, Baggerly’s collaborator in examining the papers published by the Duke genomics researchers.
“The data didn’t falsify itself; someone must have manipulated it. That becomes particularly clear when you recognize that the changes always involved altering the records of which patients responded to treatment in a way that made their predictions look better than they really were,” Coombes said to The Cancer Letter.
“I feel badly for the patients, and their families, who participated in the clinical trials that Duke University ran based on bogus research and falsified data.
“The ORI investigation has now ended with no admission of wrongdoing by Dr. Potti. The malpractice lawsuit against Dr. Potti, [his mentor, Joseph] Nevins, and Duke University was settled out of court, with no admission of guilt by anyone involved,” Coombes said. “Apparently, mistakes were made, but no one was responsible for them. That doesn’t really feel as though justice has been served.”
Words of Praise from Potti’s New Boss
Potti is practicing at the Cancer Center of North Dakota in Grand Forks. William Noyes, the lead oncologist at the center, praised Potti’s clinical skills and said that continuing attention appears to have racial undertones.
“I have followed the genomic research at Duke University for some time. The facts are that the Institute of Medicine independently reviewed all of the research data and concluded that there were systematic lapses at many levels at Duke and now the ORI has reviewed the case and concluded that Dr. Potti made mistakes but can continue to do research, if he chooses to do so. There were really no punitive damages applied to Dr. Potti,” Noyes said in response to an inquiry from The Cancer Letter.
“I have personally interacted with Dr. Potti for the past three-plus years and can say with utmost confidence that Dr Potti has always had a reputation of providing the highest quality of clinical care for his patients. His patients have always responded with the highest of recommendations per patient surveys. One patient even asked him to be an honorary pallbearer—a privilege that is rare amongst physicians.
“Hopefully, this brings closure to this issue as the persistent sensationalism seems to me to suggest an element of racial discrimination. If you are truly ‘fair and balanced,’ you will share what IOM reported that there were no signs of data manipulation, there were obvious errors made by many who were involved and that these were systems errors. Consequently, they made recommendation for all in genomic studies to follow in the future.
“ORI concluded Dr. Potti made some errors, but have concluded he should be allowed to participate in scientific studies if he so chooses.”
In May, Duke settled the suits brought by patients who were enrolled in clinical trials that were testing the technology developed by Anil Potti and his mentor Joseph Nevins, thereby avoiding having to confront embarrassing revelations about how much the university’s deans knew about the problems in the genomic research organization (The Cancer Letter, May 8).The settlement was first reported by Retraction Watch.
The text of the Federal Register notice follows:
Notice is hereby given that the Office of Research Integrity (ORI) has taken final action in the following case:
Anil Potti, M.D., Duke University School of Medicine: Based on the reports of investigations conducted by Duke University School of Medicine (Duke) and additional analysis conducted by ORI in its oversight review, ORI found that Dr. Anil Potti, former Associate Professor of Medicine, Duke, engaged in research misconduct in research supported by National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), grant R01 HL072208 and National Cancer Institute (NCI), NIH, grants R01 CA136530, R01 CA131049, K12 CA100639, R01 CA106520, and U54 CA112952.
ORI found that Respondent engaged in research misconduct by including false research data in the following published papers, submitted manuscript, grant application, and the research record as specified in 1-3 below. Specifically, ORI found that:
- Respondent stated in grant application 1 R01 CA136530-01A1 that 6 out of 33 patients responded positively to dasatinib when only 4 patients were enrolled and none responded and that the 4 CT scans presented in Figure 14 were from the lung cancer study when they were not.
- Respondent altered data sets to improve the accuracy of predictors for response to treatments in a submitted paper and in the research record by:
- Reversing the responder status of 24 out of 133 subjects for the adriamycin predictor in a manuscript submitted to Clinical Cancer Research
- switching the cancer recurrence phenotype for 46 out of 89 samples to validate the LMS predictor in a file provided to a colleague in 2008
- changing IC-50 and R-code values for the cisplatin predictor in a data set provided to NCI in 2010
- Respondent reported predictors and/or their validation by disregarding accepted scientific methodology so that false data were reported in the following:
- Blood 107:1391-1396, 2006: Describing a predictor for thrombotic phenotypes
- New England Journal of Medicine 355:570-580, 2006: Describing a predictor of lung cancer relapse
- Nature Medicine 12:1294-1300, 2006: Describing a predictor for the response to the chemotherapeutic drugs topectan and docetaxol
- Journal of Clinical Oncology 25:4350-4357, 2007: Describing a predictor for the response to the chemotherapeutic drug cisplatin
- Lancet Oncology 8:1071-1078, 2007: Describing a predictor for the response to the combination of the chemotherapeutic drugs flurouracil, epirubicin, and cyclophosphamide or docetaxol, epirubicin, and docetaxol
- Journal of the American Medical Association 299:1574-1587, 2008: Describing a predictor for breast cancer relapse
- Public Library Science One 3:e1908, 2008: Describing a predictor for the response to the chemotherapeutic drugs paclitaxel, 5-fluouracil, adriamycin, and cyclophosphamide
- Proceedings of the National Academy of Sciences 105:19432-19437, 2008: Describing a predictor of colon cancer recurrence
- Clinical Cancer Research 15:7553-7561, 2009: Describing a predictor for the response to the chemotherapeutic drug cisplatin
As a result of Duke’s investigation, the published papers listed above were retracted.
Respondent has entered into a Voluntary Settlement Agreement with ORI. Respondent neither admits nor denies ORI’s findings of research misconduct; the settlement is not an admission of liability on the part of the Respondent. The parties entered into the Agreement to conclude this matter without further expenditure of time, finances, or other resources. Respondent has not applied for or engaged in U.S. Public Health Service (PHS)-supported research since 2010. Respondent stated that he has no intention of applying for or engaging in PHS-supported research or otherwise working with PHS. However, the Respondent voluntarily agreed:
- That if the respondent obtains employment in a research position in which he receives or applies for PHS support within five years of the effective date of the Agreement (September 23, 2015), he shall have his research supervised for a period of five years;
- that prior to the submission of an application for PHS support for a research project on which the Respondent’s participation is proposed and prior to Respondent’s participation in any capacity on PHS-supported research, Respondent shall ensure that a plan for supervision of Respondent’s duties is submitted to ORI for approval; the supervision plan must be designed to ensure the scientific integrity of Respondent’s research contribution; Respondent agreed that he shall not participate in any PHS-supported research until such a supervision plan is submitted to and approved by ORI; Respondent agreed to maintain responsibility for compliance with the agreed upon supervision plan;
- that any institution employing him shall submit, in conjunction with each application for PHS funds, or report, manuscript, or abstract involving PHS-supported research in which Respondent is involved, a certification to ORI that the data provided by Respondent are based on actual experiments or are otherwise legitimately derived and that the data, procedures, and methodology are accurately reported in the application, report, manuscript, or abstract; and
- to exclude himself voluntarily from serving in any advisory capacity to PHS including, but not limited to, service on any PHS advisory committee, board, and/or peer review committee, or as a consultant for period of five years beginning on September 23, 2015.
Were Patients Harmed?
Duke argued that patients who entered these clinical studies were not harmed. The patients were, for the most part, in late stages of disease, and the predictor models were used to assign them to existing therapies.
The plaintiffs’ attorneys argued that Duke had ample opportunities to recognize that the technology tested in the three trials was fraudulent. Instead, in the spring of 2008, Duke officialssilenced a whistleblower, frustrated an NCI inquiry, and, in the fall of 2009, set up a flawed internal review of the three trials, plaintiffs alleged.
The deans who were directly involved in silencing the whistleblower later told an Institute of Medicine committee that no whistleblower had come forward from Potti’s lab.
The consent forms signed by the patients extolled the potential of Duke’s technology:
“This genomic predictor looks at hundreds of genes (pieces of DNA—a short form of deoxyribonucleic acid that contains information needed to construct and operate the human body) in your tumor. In initial studies, the genomic predictor seemed to determine which drug would be effective in a given patient with an accuracy of approximately 80%. The genomic predictor is still being tested in research studies and is therefore considered investigational.”
The whistleblower—Bradford Perez, a third-year medical student working in Potti’s lab—did more than just sound alarm.
Perez submitted a well-argued critique of flaws in the Duke genomics operation. Documents published by The Cancer Letter also show that concerns were brought to the attention of the deans in March 2008 (The Cancer Letter,Jan. 9).
Instead of a thank-you, Perez faced a full-court press led by Potti’s co-author and protector Joseph Nevins, and an all-star team of Duke officials—which included Deans Sally Kornbluth and Nancy Andrews.
Perez was assured that Nevins and Potti would go through their datasets to make sure that there were no “errors” present. Had this been done, fraud would have become evident more than two years earlier—in 2008 instead of 2010—and Duke’s clinical trials of the predictor model would have stopped months after they began.
Disappearing the Whistleblower
The Perez case is not noted in the IOM report.
According to the report, “there was discontinuity in the statistical team, which may have contributed to the research team’s failure to follow proper data management practices (Kornbluth and Dzau, 2011). Junior investigators on the team either did not recognize what was wrong or did not feel comfortable expressing their concerns even though whistle-blowing systems were in place. Some members of the laboratory did ultimately come forward with concerns about the research, but only after the University began an investigation (Kornbluth, 2011).”
Elsewhere in the report, Duke officials are quoted describing the university’s “just culture,” which encourages anyone at any level to criticize the scientific methods of a study without fear.
The report continues:
“However, the problems with the three clinical trials were not brought to the attention of the appropriate individuals within the university leadership through any of these whistleblowing channels. According to [then] Vice Dean for Research Sally Kornbluth, a number of people came forward after the university undertook its investigation and said they ‘were glad [the university was] reviewing things carefully’ (Kornbluth, 2011).
“Why no one came forward earlier, or perhaps any such concern was not forwarded appropriately, is not known, but the fact that these problems were not brought forward earlier may be an indication of the discomfort or lack of confidence that faculty and staff may have with these systems.”
The report was vetted by Duke officials, which presumably means that they reviewed it and didn’t see reasons to correct it.
Both Kornbluth and Andrews have since been promoted, and Duke officials haven’t apologized for their institution’s testimony to IOM.
An exchange of emails, obtained by The Cancer Letter, shows that Kornbluth was aware of the Perez controversy on Oct. 5, 2010, three months before the IOM committee held its first meeting and six months before the committee first met publicly with Duke officials.
At that time, Duke’s top administrators were deciding the best way to handle the Perez incident in the context of the scientific misconduct investigation. Should the Perez documents be presented to an internal Duke committee that was deciding on the scope of the misconduct investigation?
At first, Kornbluth decides that charges would be appropriate. Then she changes her mind, choosing to present the Perez materials to the standing committee, leaving it up to the group whether charges are justified.
The email is addressed to Victor Dzau, the Duke Chancellor for Health Affairs, who has since been named IOM president:
“Victor,
“My two cents: I’ve had a change on heart about this. I’ve talked to Wesley [Byerly, associate dean for research support services] at length and I think his thoughts to let the Perez stuff go in with the existing allegations (and not draft another charge) is right. I think Joe [Nevins] is going to the committee to debrief and I think the committee can then decide if they really think there is any merit in charging Joe with anything. I am feeling more and more that we may have jumped the gun with that and the answer is probably ‘no.’ Happy to discuss if you want. Sally.”
Other Documents
In another document obtained by The Cancer Letter, Holly Dressman, a top member of the Nevins and Potti operation, expressed hope that NCI officials wouldn’t request the raw data on which Potti’s predictor model for ovarian cancer was based (The Cancer Letter,Jan. 16).
Had NCI’s statisticians been able to get the code and the data they sought, they would have been able to perform basic forensic bioinformatics that would have enabled them to spot unsubstantiated claims, and worse.
In an email dated May 6, 2008, Holly Dressman, a co-author on the Duke group’s key papers, shot an email to team captain Joseph Nevins, mentor and protector of its star scientist Anil Potti.
Dressman’s email, now cited in a lawsuit against Duke, may cause a double-take:
“I am working on the [topotecan] signature in OVC and it’s a big mess. NCI wants us to resubmit the revisions again and now asking for correct Topo info…and they may want the data for their stat folks to try out like what was done with plat stuff…I am beginning to wonder if the Topo signature is real. I guess for the review, I can just hope they don’t ask for original data and just report what is in the NatMed paper.”
Here, a government-funded researcher—who, despite losing faith in the predictor used to decide which treatment an ovarian cancer patient would receive, expresses hope that NCI would relent before getting the “original” data and would settle for data published in one of the world’s premier scientific journals.
In the litigation, the plaintiffs were seeking release of thousands additional documents that Duke had previously failed to release.
A timeline of the Duke genomics scandalis available here.
