“What does it say about our national commitment to research integrity?”

.

There’s an important guest editorial by Keith Baggerly and C.K. Gunsalus in today’s issue of the Cancer Letter: “Penalty Too Light” on the Duke U. (Potti/Nevins) cancer trial fraud*. Here are some excerpts.

publication date: Nov 13, 2015

Penalty Too Light

What does it say about our national commitment to research integrity that the Department of Health and Human Services’ Office of Research Integrity has concluded that a five-year ban on federal research funding for one individual researcher is a sufficient response to a case involving millions of taxpayer dollars, completely fabricated data, and hundreds to thousands of patients in invasive clinical trials?

This week, ORI released a notice of “final action” in the case of Anil Potti, M.D. The ORI found that Dr. Potti engaged in several instances of research misconduct and banned him from receiving federal funding for five years.

(See my previous post.)

The principles involved are important and the facts complicated. This was not just a matter of research integrity. This was also a case involving direct patient care and millions of dollars in federal and other funding. The duration and extent of deception were extreme. The case catalyzed an Institute of Medicine review of genomics in clinical trials and attracted national media attention.

If there are no further conclusions coming from ORI and if there are no other investigations under way—despite the importance of the issues involved and the five years that have elapsed since research misconduct investigation began, we do not know—a strong argument can be made that neither justice nor the research community have been served by this outcome.

…..

Potti’s Actions and the Consequences

According to the ORI findings, Potti altered datasets resulting in false data being reported in many high-impact papers, in journals such as the New England Journal of Medicine and Nature Medicine, going back at least to 2005 and 2006.

This means Potti, a physician, knew that the underlying data were wrong in 2006 when he and his collaborators proposed a large clinical trial in early-stage lung cancer (CALGB 30506, aka NCT00863512, opened in 2009, with an initial target of 1525 patients), in which their Lung Metagene Score algorithm would be used to guide patient therapy.

At minimum, he knew the informed consents provided by these vulnerable patients were invalid; this remained true even when the National Cancer Institute constrained use of the LMS to evaluation only, not therapy guidance.

This also means Potti knew, as a physician, that the underlying data were wrong when they started three other Duke trials in which his genomic signatures were being used to determine therapy (listed in descending order of target enrollments):

• in breast cancer (NCT00636441, 2008, initial target 270 patients),
• in early-stage lung cancer (NCT00545948, 2007, initial target 117 patients),
• in late-stage lung cancer (NCT00509366, 2007, initial target 100 patients).

Potti knew the consents for these trials were invalid. Further, for at least one of them (late-stage lung cancer), Potti was initially the trial’s principal investigator, and yet enrolled his own patients in a trial for which he knew the data had been fabricated.

Potti knew, as a physician, that the underlying data were wrong for another proposed clinical trial:

• in late-stage lung cancer (CALGB 30702, initial target 144 patients), when he submitted the protocol to the NCI in 2009. (This trial was not approved and never conducted).

The patients enrolled in these clinical trials were lied to, given false hope, exposed to unnecessary invasive procedures to obtain tissue to prescribe or monitor therapy, and exposed to additional risks which could never result in improvements in their care or in patient care in general. These risks were real; filings in civil lawsuits—settled for undisclosed amounts in April 2015—note, for example, that “Juliet Jacobs underwent an unnecessary second biopsy [that was required for participation in the fraudulent clinical trials] that caused her great injury.”

Based on the proposed enrollments, Potti was prepared to expose over 2,000 cancer patients to these risks. Potti owed his patients a duty of care that he abused by misleading them. He repeatedly enticed cancer sufferers into trials and medical treatment, knowing that the protocols for their treatments were not based on performed research but on manipulated data.

None of this was fully discussed when Potti’s medical license was being reviewed by the North Carolina medical board in 2010-2011; many details only came out over the course of the IOM review (which lasted until 2012) and in the process of discovery in the civil lawsuits.

Every time there was an unnecessary test or procedure there was direct physical injury, loss, or damage—i.e., truly an adverse event.

Falsifying data is a dereliction of professional duty.

Subjecting human subjects to trials one knows to be useless goes against the Nuremberg Code and inflicts dignitary harm.
….

Potti put patients at risk in 2005, 2006, 2007, 2008, 2009, and 2010. Every time a new trial was proposed that would use these approaches to guide patient care, he made the choice again.

These various observations show Potti’s behavior was egregious and warrants more severe punishment than just a five-year ban on NIH funding. It’s not that ORI doesn’t have the ability to impose more stringent penalties. ORI’s website explains: “Which administrative actions, the number of administrative actions, and the length of the administrative actions depends on the seriousness of the misconduct, the impact of the misconduct, and whether the misconduct demonstrates a pattern of behavior. Administrative actions are usually imposed for three years, but have ranged from one year to a lifetime.”

Further, the regulatory authority for ORI provides, in Section V, that “If the funding agency believes that criminal or civil fraud violations may have occurred, the agency shall promptly refer the matter to the Department of Justice, the Inspector General for the agency, or other appropriate investigative body.” In other words, ORI can refer extreme cases for criminal prosecution, rather than stopping at funding bans.

We do not know whether ORI has referred Potti’s case for criminal prosecution, but their characterization of the ban as their “final action” suggests it did not. We do not have access to their reasoning. Was it because they ceded this option as part of securing a negotiated settlement?

What messages does this send? To the research community? To research institutions? To taxpayers who fund public research? And what about the patients?

As Joyce Shoffner, a patient in one of the trials, says, “If you steal a TV you’re going to be a whole lot worse off…I think this is pretty dreadful. Five years, what is five years? I’m absolutely disgusted.”

The Institutional Response

Even more worrisome than the extensive and persistent behavior of one investigator, is the institutional oversight of the research and patient treatment.
…

This case raises significant questions about how well Duke University fulfilled its institutional obligations. Some of the actions taken by its administrators could even be characterized as having the appearance of trying to thwart effective oversight. ORI—whose job it is to oversee the overseers (the university) when HHS funds are involved—did not comment on Duke’s performance in its statement. We, as outsiders, are very curious about how ORI assessed that aspect of this complex matter, what they concluded about the efficacy of Duke’s role, whether they consider that parts of the oversight system failed in places, and if so, how to fix it. These should be pressing questions for all of us.

For context, we provide a brief chronology of some major events here.

• 2007: Baggerly and Coombes first publicly reported problems with the data. We do not know of any action on Duke’s part at the time.
• 2008: Brad Perez, a member of Potti’s lab, investigated the predictors internally and was so disturbed by what he found that he repeated a year of his program, pulled his name from submitted papers and wrote a detailed letter of concerns about the conduct of the research, which he discussed with Duke administrators.

Those administrators referred Perez back to Joseph Nevins (Potti’s mentor), an individual with profound personal and professional conflicts of interest in the situation. Nevins and Potti downplayed the critique.

• 2009: Baggerly and Coombes reported (and The Cancer Letter publicized) more extensive problems with the data (September-October).

In response to an unprecedented expression of concern on the part of the NCI to Duke’s Institutional Review Board about patient safety concerns, Duke organized a review in late 2009 (before the misconduct investigation began). At the urging of Nevins, Duke administrators withheld the full extent of external critiques of the research from the reviewers, so this review lacked depth. It concluded that the data being challenged, later found to be false, were strong enough to warrant re-starting patient trials using the questioned genomic predictors.

• 2010: Revelation of a falsified CV; Potti suspended; misconduct investigation begins.
• 2011: In testimony to the IOM review committee, Duke administrators acknowledged that Nevins had been allowed to effectively control what data were examined as part of the 2009 review, but said they were not aware of problems with the data: “Some members of the laboratory did ultimately come forward with concerns about the research, but only after the University began an investigation.” The Perez report was not mentioned.
• September 2011: Civil lawsuits by injured patients filed.
• 2015: Perez’s Letter of Research Concerns, which surfaced in the process of discovery as part of the civil lawsuits, was made public by The Cancer Letter in January 2015.

Let’s review Duke’s role in this matter:

Duke University was the fiduciary for the research funding.

Duke signed the federal assurances that it would maintain an environment of research integrity and respond promptly to allegations.

Duke owns and operates a hospital that recruited and treated patients in the clinical trials. It extended practice privileges to Dr. Potti.

Duke created and disseminated video and print campaigns highlighting the research.

Duke had an interest in intellectual property in the “personalized” cancer treatment that the research promised and had licensed the technology to at least one company working to commercialize it.

Duke’s administrators and Dr. Nevins had an obligation to funders, colleagues, the research literature and patients to conduct research with integrity, yet they disregarded repeated internal and external signals that something was seriously amiss with the research underlying the clinical trials.

That last point is worth repeating: there is extensive documentation that multiple Duke administrators received credible information about serious problems in the Nevins/Potti lab as much as two years before they finally acted in 2010.
….

Because Duke’s review of Potti’s papers that might need to be retracted focused only on those with primary research data, the literature still contains commentaries such as a 2010 piece in Science Translational Medicine where Potti et al. hold their approach up as a model to be emulated and conclude:

“It could be argued that it is unwise and perhaps unethical to continue the practice of treating large numbers of unselected patients knowing that only a fraction will benefit—and further knowing that there are technologies available that have the potential to match the right drug with the right patient. We owe it to the patients, and to all of us who potentially will be patients, to change this practice if we are to make meaningful gains in implementing effective cancer therapy and winning the war on cancer.”

(Unbelievable. Potti is lecturing others on unethical clinical trials?)

Our Questions
…

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.

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.

This outcome has apparently been judged a full, complete, measured response.
Are we alone in thinking something is very wrong with this picture? (my emphasis)

Read the full editorial here.

Baggerly is a biostatistician at MD Anderson Cancer Center. Gunsalus is the director of the National Center for Professional and Research Ethics, research professor at Coordinated Science Laboratory, and professor emerita of the College of Business at the University of Illinois at Urbana-Champaign. She runs a consulting company and is the author of The Young Professional’s Survival Guide (Harvard University Press, 2012) and The College Administrator’s Survival Guide (Harvard University Press, 2006).

Baggerly Nov 13, 2015

*I thank Keith Baggerly for sending me his editorial. Anyone interested in this case should read Paul Goldberg’s Cancer Letter, “Duke Officials Silenced Med Student Who Reported Trouble in Anil Potti’s Lab”.  It’s absolutely mind-boggling to think the whistleblower (Perez) revelations were known to numerous Duke officials over a year before the Baggerly and Coombes (2009) article, and the numerous signatures that finally led to stopping the trials, only to have them restart after the whitewashed internal investigation. 

Potti training