FOLLOW the MONEY

FOLLOW the MONEY

There is no sign of let-up in the scrutiny of Stanford University and Dr. Alan Schatzberg, who chairs the University’s department of psychiatry. Since Senator Grassley started asking questions last month, the explanations offered about Stanford’s management of this faculty member’s conflicts of interest vis à vis his NIH grants and his corporation (Corcept Therapeutics) have become non-viable. The story so far can be found here and here and here.

Senator Grassley was concerned that Stanford gave him lowball information about Dr. Schatzberg’s financial stake in Corcept, and no information about Dr. Schatzberg’s realized financial gains from selling Corcept stock. Inspection of Stanford’s answers to Sen. Grassley and of the University’s faculty disclosure forms reveals that they were not designed for transparency. Dr. Schatzberg’s realized gain of $109,000 in 2005 was not reported to Stanford and so was never reported to NIH as required or to Sen. Grassley in response to the senator’s request for information. As if these were not problems enough, the University’s claims that Dr. Schatzberg kept an appropriate distance from Stanford’s NIH-supported studies of his drug were challenged here and here.

Dr. Schatzberg’s faculty disclosure information released by Stanford is artfully opaque. The real story can only be pieced together from Corcept’s SEC filings, which, I remind readers, are not provided to the public in a spirit of disclosure but because they are required by law. Here are some revealing numbers aggregated from half a dozen or so documents on the SEC website.

Between 2000 and 2007, Dr. Schatzberg’s total compensation from Corcept, at a minimum, can be documented as $401,250. He received at least $52,500 for serving on the board of directors, and $348,750 for chairing Corcept’s Scientific Advisory Board (SAB). In addition, he realized income through selling shares worth $109,000. That adds up to more than $510,000.

While Dr. Schatzberg was earning almost $350,000 from Corcept for his work on the SAB, he was also being paid by NIH to do overlapping scientific work. Where was the boundary? The Stanford clinical trials of Dr. Schatzberg’s drug closely resembled Corcept’s trials in dosage, duration, and outcome measures. As the NIH-funded Principal Investigator at Stanford and as chair of the Corcept SAB, Dr. Schatzberg is accountable for the design of the trials conducted both at the University and by the corporation. To an exaggerated degree, the Stanford trials were touted as positive, whereas the Phase III trials conducted by Corcept were all negative. The scientific rationales put forth by Dr. Schatzberg through his NIH-supported studies of related clinical research questions were used by Corcept in raising capital and in pleading with the FDA for fast-track status. Many of the claims from these NIH-supported studies had a bearing on the potential market for Dr. Schatzberg’s drug – his expansive estimates of the prevalence of psychotic depression, for instance, and his unwarranted claim that his drug acted to “re-set” a key, depression-related, brain-hormone system on which his drug acts. There was even a revolving door for junior faculty between Stanford and the corporation. One junior faculty member worked on the Stanford studies, then went full-time to Corcept for about 2 years as its Chief Medical Officer, then returned to the Stanford faculty ranks. Now another former junior faculty member is Corcept’s CMO. Dr. Schatzberg has the power to influence the academic careers of these individuals. Hello! Is there a conflict of interest here? Does it seem that there really was no boundary?

Then there is information in the SEC filings about stock held in the name of Dr. Schatzberg’s two children. In January 2002 Dr. Schatzberg was listed as the beneficial owner of 3,605,215 shares. This number included 360,000 shares held of record by each of his two children, over which Dr. Schatzberg had voting control. By December 31, 2004 the number of shares declared for each child had contracted to 300,000. A reasonable inference is that 60,000 shares may have been sold on behalf of each child at some time between early 2002 and the end of 2004. It may be that the original count of 360,000 shares per child was stated in error, but that seems unlikely. Corcept consummated its stock IPO in April 2004 at a price of $12.00 per share. When Dr. Schatzberg sold his own shares in 2005 he realized a price of $7.00 per share. We don’t know for sure what price any shares sold on behalf of Dr. Schatzberg’s children may have brought, because these are apparently not listed as insider trades. Up to the end of 2004 they could have fetched anything between $11.00 and around $5.50. If they fetched $7.00 then as much as $840,000 may have been realized for the Schatzberg family. The cost to Dr. Schatzberg for these 120,000 shares was $40.

So now we are looking at something between at least $510,000 and potentially around $1,350,000 realized by Dr. Schatzberg and his family from Corcept between 2000 and 2007. As I detailed before, Dr. Schatzberg also made 2 determined but unsuccessful runs at selling shares for $7-11 million during the corporation’s IPO attempts. Keep in mind that all of this would be OPM – other people’s money. And Dr. Schatzberg was already being paid by Stanford and NIH. What did Dr. Schatzberg contribute to the greater good in return for this corporate bonanza? You be the judge. To many appalled observers it looks like gaming the system.

This case bids fair to become a landmark that convinces NIH and the Universities to get real about academic-corporate boundaries. Senator Grassley issued a new round of questions to both Stanford and NIH yesterday. And as Ed Silverman reports this afternoon, Stanford has now replaced Dr. Schatzberg as Principal Investigator on the NIH grant.

MANAGING CONFLICTS of INTEREST at STANFORD

MANAGING CONFLICTS OF INTEREST AT STANFORD

The case of Stanford University and Dr. Alan Schatzberg, chairman of Stanford’s department of psychiatry, continues to raise questions. You can see previous discussions here. The questions concern transparency at the academic-corporate boundary, reporting conflicts of interest to NIH, and Stanford’s “management” of a faculty member known to have a significant conflict. The conflict involves a company Dr. Schatzberg founded (Corcept Therapeutics), a drug called mifepristone that Corcept has in clinical trials for depression, and NIH-supported studies of the same drug at Stanford.

Stanford’s position is that Dr. Schatzberg “has not been involved in managing or conducting any human subjects research involving Mifepristone …” Dr. Schatzberg’s 2006 published disclaimer stated “…Dr Schatzberg played no direct role in the recruitment, assessment, or follow-up of subjects enrolled in this study. Dr Schatzberg was not directly involved in the analysis of data stemming from this research.” Stanford represented that this disclaimer applies also to earlier publications with Dr. Schatzberg as co-author.

This disclaimer is hardly credible, considering the responsibilities of NIH-funded Principal Investigators. I pointed out many of the inconsistencies before. Now there is new evidence that Dr. Schatzberg failed to maintain an arm’s-length relationship to the projects at Stanford.

In a 2008 review article, Dr. Schatzberg discussed the Stanford projects in ways that contradict the claim of an arm’s-length relationship. This article acknowledged Dr. Schatzberg’s NIH grant support at Stanford. Corcept Therapeutics was not acknowledged as a source of funding. The first concern is that, if Dr. Schatzberg’s relationship to the Stanford studies is as Stanford claimed, then he has no business publishing a NIH-supported review article that portrays his drug’s prospects in a favorable light. Hello! Is there a conflict of interest here? Review articles that assess a field and synthesize data form a crucial part of science that has to be off-limits to Dr. Schatzberg just as much as assessing patients in one of his clinical trials would be. His many favorable, even exaggerated, articles, reviews and commentaries since he founded Corcept should have come under this proscription. So much for Stanford’s “management” of the conflict. Dr. Schatzberg certainly had a role in managing the research supported by NIH at Stanford – he managed the climate of scientific opinion for his drug and he managed the tone of the NIH-supported publications from Stanford.

Second, Dr. Schatzberg made a claim of efficacy for his drug that differed from what was originally reported in an NIH-supported Stanford study. He claimed a 31% decrease of symptom ratings with a scale called the BPRS. The original report does not confirm that claim. From the published data tabulated in the report, the reduction of symptom severity was 20%. Readers can easily check that for themselves. So, in a current scientific review article Dr. Schatzberg deviated from the published record. He also inflated by half the efficacy estimate for his drug. Hello! Is there a conflict of interest here?

Third, this false claim indicates that Dr. Schatzberg performed and published his own reanalysis of the primary data from an NIH-funded Stanford study. He didn’t get the number 31% from the published article. Yet Stanford says he had no part in managing or conducting the research or in analyzing any data. So here we have an NIH-funded Principal Investigator, with a clear conflict of interest, who supposedly remains at arm’s length from the project, accessing the primary data files, running a new analysis himself, and publishing an exaggerated new efficacy result for his drug that does not match what he published previously as a co-author. That is inconsistent with Stanford’s defense of Dr. Schatzberg. Hello! Is there a conflict of interest here?

Fourth, in this review article Dr. Schatzberg presented the first data on mifepristone blood levels in a peer reviewed journal, along with an elaborate scientific argument for the importance of the blood level as a moderator of response. These blood level data came from Corcept’s clinical trials, but the target blood level stated by Dr. Schatzberg did not correspond to SEC filings and press releases from Corcept. The administrative issue here is how Stanford justifies the presentation and discussion of original scientific data by a Principal Investigator who is supposedly insulated from the scientific work of the project in order to avoid bias. Dr. Schatzberg’s discussion of the new data and his scientific arguments about blood levels form a crucial part of the scientific platform for his drug’s current prospects, and as such must be off limits, just as assessing patients in one of his clinical trials would be off limits under Stanford’s policy. Hello! Is there a conflict of interest here?

This current example undercuts the assertions by Stanford and Dr. Schatzberg that his conflicts of interest have been “managed” by the University. Dr. Schatzberg may not have assessed any patients in Stanford’s trials of mifepristone, but he has had the lead role in responding to scientific critiques, where he clearly was the manager. He also has had the lead role in selling the mifepristone story to the scientific community and in shaping the tone of the NIH-supported Stanford publications that Corcept relied on to raise capital. Hello! Is there a conflict of interest here? How does Stanford justify these academic-commercial boundary violations, and why does NIH not act on the known conflicts of interest? That was Senator Grassley’s question to Dr. Zerhouni today.

STANFORD, SCHATZBERG and CORCEPT THERAPEUTICS: RECOGNIZING and MANAGING CONFLICTS

STANFORD, SCHATZBERG and CORCEPT THERAPEUTICS: RECOGNIZING and MANAGING CONFLICTS

The case of Stanford University and Dr. Alan Schatzberg, chairman of Stanford’s department of psychiatry, has been in the news for a week. Senator Grassley raised concerns about conflicts of interest, reporting of same, and Stanford’s policies. In play are a company called Corcept Therapeutics that Dr. Schatzberg founded, and a drug called Mifepristone or RU 486 that is in clinical trials for a severe form of depression. Interest in this case is especially high because Dr. Schatzberg is the president-elect of the American Psychiatric Association. Daniel Carlat, Clin Psych, and University Diaries have had cogent commentaries on the wider implications of this breaking issue.

The University issued a statement in response to Sen. Grassley. This statement asserted that Dr. Schatzberg has fully complied with the University’s rigorous conflict of interest policy and that Dr. Schatzberg “has not been involved in managing or conducting any human subjects research involving Mifepristone, a pharmaceutical that Corcept licenses for the treatment of psychotic major depression.”

Stanford’s account of Dr. Schatzberg’s arm’s-length role in Stanford’s NIH-supported studies of RU 486 (mifepristone) for depression is questionable, if not disingenuous. Dr. Schatzberg’s patent application filing for use of RU 486 in depression occurred in 1997, and he founded the corporation Corcept Therapeutics in 1998. He was a member of the board of directors from 1998 to 2007. He has chaired the corporation’s scientific advisory board since 1998.

There is reason to believe that Dr. Schatzberg had a key role in Stanford’s clinical trials of Corcept’s drug reported in 2001, 2002, and 2006. He was a co-author on all three publications, and there was no disclaimer about his role until 2006. This disclaimer is hardly credible. As Principal Investigator on the NIH grants, Dr. Schatzberg was expected to supervise the junior faculty and research staff at Stanford who recruited, assessed, and treated patients in the studies of RU 486. He was responsible for the choice of outcome measures, about which questions have been raised. He was responsible for the quality of the reported data analyses, which were, frankly, inexpert, when they were provided at all. Above all, he was responsible for the tone of the NIH-supported Stanford publications that claimed Corcept’s drug is effective.

If there were any doubt that Dr. Schatzberg’s hands were all over these Stanford studies, one only has to see the record of his leading role in responding to scientific critiques of their design, execution, analysis, and interpretation. He was clearly the manager.

Moreover, the record is clear that Corcept relied on the NIH-supported Stanford publications for positive claims to enable the corporation to raise capital (well over $100 million by now, with nothing to show for it). Corcept’s own Phase III clinical trials have been uniformly negative. For this strategy to succeed, the Stanford trials had to be portrayed as positive. As Paul Jacobs detailed in the San Jose Mercury News in 2006, using independent statistical experts, Dr. Schatzberg and his Stanford/Corcept colleagues made seriously exaggerated claims for the drug’s efficacy in their 2001 and 2002 publications. These exaggerated claims have been assiduously repeated by Dr. Schatzberg, by Stanford faculty members answerable to him, and by academic members of Corcept’s scientific advisory board in many scientific journals and textbooks. All these testimonials are compromised. The effect of these repeated, unjustified, claims is to raise the profile of the corporation and of the drug. It amounts to public relations and branding through academic outlets. Roy Poses on this site has dissected the scientific credibility of claims for the utility of RU 486 in depression.

Far from being removed from the scientific debate about Corcept’s drug, Dr. Schatzberg has had the leading role in “selling” the story to the scientific community, in “defending the brand” against scientific criticisms, and in providing his corporation a plausible story line to attract new capital. It was Dr. Schatzberg who talked about how the drug “may be the equivalent of shock treatments in a pill” in a 2002 Stanford press release. There is no clear boundary between Dr. Schatzberg’s NIH-supported academic roles and his service to the corporation he founded. As for not being involved in the management of the Stanford projects, Dr. Schatzberg acknowledged to Paul Jacobs of the San Jose Mercury News “that he has considerable influence over the junior faculty members doing the studies. As chairman of psychiatry, he helps set their salaries and can affect their career advancement. And he continues as a co-author of the resulting papers.”

I have already commented on Dr. Schatzberg’s efforts to sell large parcels of Corcept stock during the company’s IPO attempts. Had these efforts been successful, Dr. Schatzberg would have benefited by $7-11 million, while still retaining over 2 million shares of Corcept stock. This aspect of the issue troubles many people. In our capitalist system, considered so necessary for developing innovative drugs, nobody complains when an entrepreneur makes a fortune inventing a useful product. Dr. Schatzberg’s apparent intent, however, was to reach for the reward before contributing any product of redeeming social value. The prospects of RU 486 succeeding as a useful treatment of psychotic depression are close to zero. People view such behavior as gaming the system. Moreover, under Stanford’s existing rules, these projected stock sales might never have been reported.

Are these significant conflicts of interest? Yes. Have they “influence(d) the conduct of medical research” at Stanford (quoting now from Stanford’s June 24 statement)? Yes. Dr. Schatzberg’s NIH grants dovetail with the efforts of his corporation, and the corporation used data from the NIH-grant-supported projects for commercial promotion. Had the corporation not existed, these particular grants likely would not have been initiated or would have had different scientific emphases. Has Dr. Schatzberg’s research “been compromised by his financial stake”? Yes. His academic publications on depression and RU 486 are compromised by exaggerated and self-serving claims for his corporation’s drug. Senator Grassley is right: it is time for Stanford to get real about corporate-academic boundaries.

Conflicts of Interest at Stanford: the Mifespristone Studies

Paul Jacobs' series on conflicts of interest at Stanford University also included a detailed case study.

Its subject was Dr Alan F Schatzberg, Chair of the Psychiatry Department at the Medical School. Dr Schatzberg is currently running a federal grant on mifepristone as a treatment of depression. Dr Schatzberg has previously been the senior author of two related articles:
- Belanoff JK, Rothschild AJ, Cassidy F, DeBattista C, Baulieu E, Schold C, Schatzberg AF. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol Psychiatr 2002; 52: 386-392. (Link here.)
- Flores BH, Kenna H, Keller J, Solvason HB, Schatzberg AF. Clinical and biological effects of mifepristone treatment for psychotic depression. Neuropsychpharmacol 2006; 31: 628-636. (Link here.)

The first article disclosed that the study was supported by a grant from Corcept Therapeutics, and that Schatzberg has "a financial interest" in the company, as did other authors.

The second article disclosed support from the National Institutes of Health. It further noted, "Dr Alan Schatzberg is cofounder of Corcept Therapeutics and is the only author involved in this resubmission who has any financial interest in the company. However, Dr. Schatzberg continues to be full-time faculty at Stanford University. Dr. Schatzberg played no direct role in the recruitment, assessment, or follow-up of subjects enrolled in this study. Dr. Schatzberg was not directly involved in the analysis of data stemming from this research."

Nonetheless, Jacobs' article showed that Schatzberg's ties to Corcept Therapeutics were extensive:

With the backing of Silicon Valley biotech investors, Schatzberg and [Dr Joseph K] Belanoff [a research fellow in psychiatry] in 1998 founded Corcept Therapeutics.

Belanoff became the company's full-time chief executive officer. Schatzberg took a seat on the board of directors and a part-time post as chairman of the company's scientific advisory board, a job that now pays him $60,000 a year. He and his family were granted 3 million Corcept shares for $1,000 -- today worth nearly $12 million.

After the company was formed,

Schatzberg decided he could no longer play a direct role in RU-486 studies in depression. But he remained principal investigator with overall responsibility for NIH grants that have paid for ongoing Stanford research on the drug Corcept hopes to market.

Schatzberg says he helped design the RU-486 studies being conducted on campus but leaves it to others to recruit patients, administer treatments and analyze results. Monitoring committees at NIH and Stanford review the studies to ensure patient safety.

However, Schatzberg acknowledges that he has considerable influence over the junior faculty members doing the studies. As chairman of psychiatry, he helps set their salaries and can affect their career advancement. And he continues as a co-author of the resulting papers.

After the study reported by the first paper above was performed,

on the strength of these early findings, Corcept had raised $29 million from private sources. Four months later, the results of the five-patient pilot study were published in a scientific journal, claiming 'a rapid reversal of psychotic depression.'

Just before Christmas that year, Corcept filed plans with the Securities and Exchange Commission to raise as much as $90 million in an initial public stock offering. While the company waited to issue stock, Schatzberg, Belanoff and others reported in the journal Biological Psychiatry the results of the larger Corcept-sponsored study of RU-486 in 30 patients at six academic centers, including Stanford.

However, some strongly criticized this study.

Bernard Carroll recalls first reading the Biological Psychiatry study in his home-office in Carmel, where he runs his non-profit institute, the Pacific Behavioral Research Foundation.

'The spin was unmistakable,'' Carroll said. His reaction, he said, was 'sadness and dismay at the low standards evident in the report and in the editorial commentary.'' That commentary, written by the journal's editors, described the work as a possible 'paradigm shift in the treatment of depression.'

Later that afternoon, he got a call from his friend Robert Rubin, then a professor of psychiatry at Drexel University and Allegheny General Hospital in Pittsburgh. The two had become self-appointed guardians of scientific rigor in psychiatric research -- gadflies who periodically fire off salvos to journals to complain about papers that don't measure up to their standards.

They sent such a letter to Biological Psychiatry. They criticized Schatzberg for claiming the drug 'may be the equivalent of shock treatments in a pill.' They accused the authors of 'obfuscation' and the editors of ignoring the study's 'fatal flaws.'

Schatzberg and Belanoff responded, saying the letter was an 'ad hominem attack,' and that Carroll and Rubin had 'cut and pasted snips of quotes . . . and mis-characterized what we said.'

Weighing what to do with this unusually heated exchange, the journal's editors sent the correspondence to four outside, anonymous reviewers, who split, two and two, on whether the letter and response should be published. In the end, the editors decided not to print the exchange, setting the stage for Carroll and Rubin to go public in Puerto Rico [at the 2004 meeting of the American College of Neuropsychopharmacology].

[There] Schatzberg's critics publicly unveiled their critique of his work in the form of a poster -- really a scientific paper in outline form, pinned to a board in an exhibit hall.

The contents were explosive.

The poster, by Drs. Bernard J. Carroll and Robert T. Rubin, systematically picked apart the conclusions in three published studies of RU-486 in depression, two by Schatzberg and his colleagues, one by an independent group.

But in a departure from the usual give and take of scientific debate, the poster quoted positive public statements about the drug by Schatzberg and other researchers and juxtaposed those statements against the individual's financial interest in Corcept.

There, for example, was Schatzberg saying RU-486 may be 'the equivalent of shock treatments in a pill' and a statement pointing out that he owned 3 million shares of Corcept stock. The point was hard to miss: Researchers with a financial interest were expressing 'considerable enthusiasm' for a treatment of questionable effectiveness.

The poster was seen by many of the top brain scientists in the country, people whose opinions matter deeply to Schatzberg as well as his critics. Carroll, former head of psychiatry at Duke University and now semi-retired in Carmel, recalls that people came up to him during the session, slapped him on the back and said, 'It's about time somebody said this.'

But he and Rubin soon learned that other members, Schatzberg among them, were furious. A lawyer for Corcept says the ACNP admonished Carroll and Rubin for their conduct. Both Carroll and Rubin say they were faulted for making their criticisms public, not for the content of the presentation.

Even now, Schatzberg can hardly contain his anger. 'Those that are critical,' he said, 'ought to be careful about impugning others.'

Two independent experts asked by the Mercury News to review the three key RU-486 studies co-written by Schatzberg side with Carroll and Rubin.

University of California-San Francisco Professor of Medicine Stanton A. Glantz, the author of 'Primer of Biostatistics,' found several statistical errors in the papers he was asked to look at.

'These are elementary statistical methods,' he said. 'They have applied them incorrectly.' The result was to 'bias their results toward reporting an effect when the data doesn't justify that. Scientists shouldn't make these dumb mistakes.'

The other expert is Steven G. Self, a professor at the University of Washington, who heads the program in biostatistics and biomathematics at the Fred Hutchinson Cancer Research Center in Seattle.

Commenting on the 2002 paper in Biological Psychiatry, he said, 'there is no evidence at all' for a meaningful difference in the response of patients given high doses of RU-486 and those given a very low dose presumed to have no effect at all. All you have to do is look at the data, he said, to see this. 'No formal statistics are required.'

Schatzberg said that applying statistical analyses to these small, preliminary case studies is 'absolutely silly.' And Corcept CEO Belanoff agrees.

I will add a few technical comments. The 2002 Biological Psychiatry paper was an "open-label trial" in which all 30 patients got some dose of mifepristone. It had no control which received placebo or another drug. Given the unpredictable course of depression, it is impossible to tell whether any differences seen in groups receiving different doses of the drug were due to effects of the different doses, or the natural variability in the course of disease across patients. Many authorities on evidence-based medicine would hugely discount studies of drug or other treatments that did not randomize patients to the treatment of interest or some comparison treatment. (See, for example, Guyatt GH, Sackett DL and Cook DJ. Users' guides to the medical literature. II. How to use an article about therapy or prevention. A. Are the results of the study valid? JAMA 1993; 270 2598-2601. )

The study is so small, moreover, that any differences could simply have been due to random noise. Thus, the study's conclusions that "mifepristone appeared to be effective" seem to go beyond the evidence provided.

Furthermore, the disclosure in this article seems not to convey the degree of financial involvement of Dr Schatzberg in Corcept Therapeutics.

The important investigative reporting by Paul Jacobs in the Mercury News gives us an important example again of how pervasive are conflicts of interest among leaders of academic medicine. Unfortunately, the pervasiveness of such conflicts means that everyone now ought to be skeptical about in whose interests academic medicine now speaks and acts.

COMMERCIAL BIAS at STANFORD and CORCEPT

COMMERCIAL BIAS at STANFORD and CORCEPT

Stanford University has replaced Dr. Alan Schatzberg as Principal Investigator on his NIH grant that studies psychotic depression. This step followed persistent questions from Senator Grassley about conflicts of interest and financial disclosure. Dr. Schatzberg’s drug mifepristone has been in NIH-supported clinical trials at Stanford and in FDA-monitored trials sponsored by Corcept, the company Dr. Schatzberg founded.

The University emphasized “We want to put to rest confusion about the integrity of the research involving mifepristone.” Questions did arise following NIH-supported publications from Stanford in 2001 and 2002. Neither one found significant evidence of efficacy, yet both were repeatedly touted by Dr. Schatzberg and his associates as positive. The 2001 report had no significant findings even after attempts to cherry-pick the data. In the 2002 report the data were so weak that Dr. Schatzberg elected to present no statistical analyses of outcome at all. We now know from Corcept’s three negative FDA-monitored Phase III trials that the early challenges to mifepristone’s efficacy had merit (see Abstract #63). As Dr. Schatzberg should know, wishful thinking and hand waving are no substitute for quality data that are rigorously analyzed. Dr. Schatzberg is accountable for the unwarranted positive tone of those early publications. His later promotional claims reveal a commercial bias that has no place in academic medicine.

Scientists are required to present both the positive and the negative aspects of their research “fully and honestly.” Here is one example of this code (see item 2). Here is another (see item 15). The standard does not change when commerce is involved. The standard applies in review articles as much as in original reports. Did the Stanford-Corcept group meet this standard? That is the issue Stanford now confronts.

In a 2003 textbook that he coauthored (Manual of Clinical Psychopharmacology), Dr. Schatzberg made a clearly biased claim. He stated “Two recent studies of … (mifepristone) … by our group have demonstrated efficacy in the treatment of psychotic depression.” He was referring to the 2001 and 2002 Stanford-NIH publications. Dr. Schatzberg went on to state that “The effects were more pronounced on the psychosis than on the depression, but both were significantly improved within 7 days.”

The claim of “demonstrated efficacy” is categorically false. It may be fraudulent. Neither study achieved any accepted evidence of efficacy. The second claim also is categorically false. No quantitative data on significant improvement of psychotic symptoms or depression severity exist in the two studies for drug over placebo. Lack of efficacy is what the investigative journalist Paul Jacobs exposed so well, with the consultation of independent statisticians, in the San Jose Mercury News July 10, 2006.

These false claims in a well-known textbook promoted a positive climate of opinion for Dr. Schatzberg’s drug in the period leading up to Corcept’s planned IPO. Through the textbook, Dr. Schatzberg also promoted positive professional expectations in advance of the marketing of his drug. Moreover, in this American Psychiatric Press publication Dr. Schatzberg did not disclose his large financial interest.

The pattern of exaggerating positive trends in the data while suppressing mention of negative analyses has become a trademark of Stanford-Corcept publications. Dr. Schatzberg made similar unwarranted claims in a 2003 journal article. In 2006 Dr. Schatzberg did likewise in another APA Press publication (The American Psychiatric Publishing Textbook of Mood Disorders). Once again, Dr. Schatzberg used an APA Press textbook to talk up his drug’s prospects. Once again, Dr. Schatzberg did not disclose his own financial interest.

In 2006, Corcept’s CEO (Dr. Joseph Belanoff) and the former Chief Medical Officer (Dr. Charles DeBattista) published a review article on use of mifepristone in neuropsychiatric disorders. In violation of the journal publisher’s policy, the article was sourced only to Stanford University. These current and past Corcept officers did not disclose their financial interest or their relationship to the corporation. They highlighted the use of mifepristone in psychotic depression. Referring to the 2001 Stanford-NIH trial, they claimed “all five patients showed a substantial improvement in depression.” This claim is categorically false. The question of fraud arises again.

These examples illustrate what I have termed commercial promotion and branding through academic outlets. In all, 13 scientific journals, 4 textbooks, and other media have been tainted by these and similar misrepresentations. These biased claims in reference to the Stanford-NIH trials were also featured in press releases and press interviews while Corcept was raising private and public capital.

This pattern of bias raises questions of ethics, and of possible fraud. One could make the case that the misrepresentations described here do not fall under the safe harbor provisions of US securities law. It is one thing for entrepreneurs to speculate giddily about the potential of their product if the available scientific data are presented accurately (“fully and honestly”). In that circumstance, caveat investor applies. But it is an altogether different matter when entrepreneurs misrepresent the available scientific data by emphasizing positive trends while suppressing the inconvenient, negative aspects of the data. That is what Corcept did in discussing the 2002 Stanford-NIH trial in its SEC filing March 19, 2004 leading up to the IPO. That is also what Dr. Schatzberg and his associates did in the examples given above.

Dr. Schatzberg is slated to become president of the American Psychiatric Association in 2009. The APA would do well to reconsider his fitness for that office. We would have expected Dr. Schatzberg, who is also President of the American Psychiatric Press, the publishing arm of the APA, to understand that he and his corporate associates should discuss their scientific data “fully and honestly,” while being transparent about their competing financial interests. As for Stanford University, these academic biases and systemic conflicts of interest signal the need for a fresh look at the academic-corporate boundary.

SCHATZBERG DISCLOSURE

SCHATZBERG DISCLOSURES

Questions continue to buzz about Dr. Alan Schatzberg’s and Stanford’s claims that he complied with the university’s disclosure requirements. Dr. Schatzberg is chair of Stanford’s department of psychiatry and the founder of a company called Corcept Therapeutics. I have commented previously on the University’s (mis)management of Dr. Schatzberg’s conflict of interest vis a vis Corcept and his NIH funding.

The two most informative documents released by Stanford University are dated 23 May 2008 and 25 June 2008. The first is an amended response to Senator Charles Grassley. The second is a public statement concerning Sen. Grassley’s investigation of Dr. Schatzberg through the Senate Finance Committee.. The complete texts are available on-line here: http://ucomm.stanford.edu/news/052308conflict_of_interest.pdf (1)

and here http://ucomm.stanford.edu/news/062508conflict_of_interest.pdf (2)

Additional perspective is to be found in an article in the Stanford Daily here:
http://www.stanforddaily.com/article/2008/7/10/senatorTargetsSchatzbergForConflictOfInterest (3)

Stanford’s policy requires that

“Disclosure of potential conflicts of interest at the time of any transaction,
such as when the faculty member receives a research grant or gift or has
intellectual property licensed, is a critical component of our conflict of
interest policy. Transactional disclosures of conflicts of interest are required
when submitting a grant, negotiating a contract, during licensing activities,
submitting protocols for human subjects research or animal research, entering
into material transfer agreements or collaboration agreements, receiving gifts
or entering into procurement activities. … Our standard for a significant
financial interest is whether the faculty member has received $10,000 or more in
income, holds $10,000 or more in equity in equity for publicly traded companies
or has any equity if the company is privately held. This ad hoc disclosure is
used to mitigate, manage or remove such specific conflicts, and, for all
research funded by NIH, as a basis for reporting to NIH. All such conflicts are
also reported in the annual disclosure, and thus are also part of the University
information on conflict of interest (emphases added) (1).

Likewise, the Stanford Daily reported that

“the University said in its letter to Grassley that it holds a “zero-dollar
threshold for disclosure.” This requires that faculty members divulge any and
all financial gains made through outside interactions that could have bearing on
what they are doing on campus.” (3)

The sale of Corcept Therapeutics stock by Dr. Schatzberg in 2005 was not reported to the University. (1) Dr. Schatzberg’s attempted sales of stock in 2002 and 2004 in connection with Corcept’s planned stock IPOs also were not reported to the University. (1) Proceeds of the 2005 sale to Dr. Schatzberg were over $109,000. Projected proceeds of the failed attempts to sell stock during the IPOs were $7-11 million. In terms of the policy described above, these must be considered “transactions” and “income” and “financial gains.” Stanford did not document compliance by Dr. Schatzberg with University policy. The stock sale is not mentioned in Dr. Schatzberg’s 2005 disclosure to the University. (1) Indeed, Stanford prevaricated on this issue by stating “…information about his stock ownership and stock sales was publicly disclosed through SEC filings and is available online through financial reporting services.” (2)

This explanation is laughable. Since when does a University rely on SEC filings and online financial reporting services to learn about the transactions and financial conflicts of its faculty members in order to discharge its fiduciary duty to disclose these transactions to NIH?

Even worse, the American Psychiatric Association has parroted Stanford’s assertion that Dr. Schatzberg made the required disclosures. In an interview with the New York Times, Dr. Nada L. Stotland, president of the psychiatric association, said the group had studied Mr. Grassley’s letter and Stanford’s response and agreed with Stanford. Dr. Schatzberg will take over as president of the association as planned, she said. The association and the University here are being disingenuous – treating an ethical issue as a technical legalism. But even on legally technical grounds their case fails. Is that the standard that Stanford and the APA wish to state for the record?

Once again, it is time for Stanford to get real about the boundary between commerce and academia. And, in view of the unjustified promotion of their commercial interest by Dr. Schatzberg and his corporate associates through academic outlets, it is time for the American Psychiatric Association to grasp the nettle and to reconsider Dr. Schatzberg’s fitness to serve as president in 2009.

SCHATZBERG, STANFORD and the AMERICAN PSYCHIATRIC ASSOCIATION

14 July 2008

SCHATZBERG, STANFORD and the AMERICAN PSYCHIATRIC ASSOCIATION

The chairman of psychiatry at Stanford University, Dr. Alan Schatzberg, is still in the news for his problems at the boundary of commerce and academia. The New York Times reported that Dr. Schatzberg believes constraints on researchers trying to develop drugs “will mean less opportunities to help patients with severe illnesses.” Just as patriotism is the last refuge of the scoundrel, so patient welfare is the last refuge of the dodgy medical entrepreneur.

What exactly does Dr. Schatzberg mean by “constraints”? Does he object to transparency as a “constraint”? Would he feel “constrained” by the need to disclose his stock sales to his academic institution? The Stanford Daily commented recently that Stanford policy “requires that faculty members divulge any and all financial gains made through outside interactions that could have bearing on what they are doing on campus.” One reason for this requirement is so that the institution can disclose these financial dealings to NIH, which funds Dr. Schatzberg’s academic work that dovetails with his corporation’s research. It is difficult to reconcile Dr. Schatzberg’s protestations of compliance with the non-reporting of his stock sale valued at over $100,000 (not to mention his efforts to sell stock valued at $7-11 million).

Would Dr. Schatzberg and his corporate associates feel “constrained” by the requirement to disclose their competing financial interests when touting the company’s drug in scientific journals, textbooks, educational media, and press interviews? The record is clear that they have repeatedly failed to do so.

Would Dr. Schatzberg and his corporate associates feel “constrained” by the canons of science that frown on exaggerated claims and hyperbole in the service of their business enterprise? The record is clear that they have repeatedly overstated the evidence for their drug’s prospects. These exaggerated claims were touted by the corporation when raising capital.

Would Dr. Schatzberg feel “constrained” by the societal expectation to refrain from gaming the entrepreneurial reward system? He appeared to believe he was entitled to cash out $7-11 million of other people’s money before actually producing anything of redeeming social value.

If this is what Dr. Schatzberg means by “constraints” then his fitness for the office of president of the American Psychiatric Association needs to be reconsidered.

FOLLOW the MONEY, Part II

FOLLOW the MONEY, Part II

Recently we looked at some financial aspects of the boundary between Stanford University and Corcept Therapeutics. Dr. Alan Schatzberg, the chair of Stanford’s psychiatry department, received at least $510,000 from Corcept between 2000 and 2007. Senator Grassley asked why NIH received no disclosure from Stanford of Dr. Schatzberg’s realized gain from selling Corcept stock while he was Principal Investigator on a related NIH grant. The Senator also remarked on Stanford’s lowball estimate to him of Dr. Schatzberg’s equity in Corcept, currently between $5 million and $6 million.

Dr. Schatzberg is not the only academic to benefit from Corcept. Dr. Charles Nemeroff, a member of Corcept’s scientific advisory board, also did well. He exercised options to buy 60,000 shares on joining the board in 1998. Dr. Nemeroff diligently promoted Corcept’s drug. Following the style documented for Dr. Schatzberg, Dr. Nemeroff emphasized weak positive trends in the data while suppressing inconvenient negative analyses. In the fall of 2002, Dr. Nemeroff referred to the Stanford-NIH trials as “impressive studies indicating that ... (mifepristone)...is very effective in the treatment of psychotic depression.” The claims “impressive” and “very effective” are indefensible, and may even be fraudulent. Dr. Nemeroff’s exaggerated promotion occurred while the company prepared for its IPO, but he did not disclose his financial stake. Right after the 6-month SEC-mandated lockup period expired, Dr. Nemeroff sold 20,000 shares for $137,500. His cost was $6.60. Help me, what is the right term for this behavior?

A second member of the team who did well is Dr. Joseph Belanoff, Corcept’s co-founder and CEO. Like Dr. Schatzberg, he received around 3 million shares in 1998. Dr. Belanoff began selling as soon as the lock-up period ended. Between November 2004 and November 2006, Dr. Belanoff sold approximately 10,000 Corcept shares each month, realizing over $1 million. His cost for all those shares was around $80. An on-line financial service listed 6 additional quarterly sales, each of 30,000 shares, which netted over $900,000. Dr. Belanoff also received an ample corporate salary. His documented salary increased from $310,500 plus a 10% bonus in 2003 to $1,643,760 in salary ($411,008), bonus ($102,752), and stock options ($1,130,000) in 2007. Not bad, for someone with modest academic credentials.

Stanford University itself has a financial stake. Following a licensing fee of $47,000 that was paid to Stanford in 1999 along with 30,000 shares of stock, Corcept has been obligated to make non-refundable royalty payments of $50,000 a year. That adds up to $497,000 through 2008. Additional payments up to $250,000 are due to Stanford when certain drug development milestones are reached. Stanford has stated that it long ago divested itself of the Corcept stock. However, an on-line information service lists Stanford as a major shareholder as recently as 31 March 2008, with over 47,000 shares in the name of the Board of Trustees. In a second agreement, Stanford receives a $20,000 licensing fee, 1000 shares of Corcept stock, $10,000 a year in non-refundable royalties, and potential milestone payments of $350,000. All of this is in advance of any marketing of products by Corcept. So, Stanford is not exactly a disinterested administrator of the academic-corporate boundary between Dr. Schatzberg, NIH, and Corcept.

We should also note some unusual events involving Corcept stock movements. On 15 August 2005 Corcept stock received a research broker upgrade. Heavy selling followed the upgrade (volume was 613,000 shares, 31 standard deviations above the mean for the previous 10 trading days). For non-statistician readers, 3 standard deviations would tell us that the spike is almost certainly not consistent with the historical fluctuations in volume. So, a spike of 31 standard deviations means any such probability is astronomically small. The stock price moved up 34% from the previous day but quickly sank again. That same day, Dr. Schatzberg sold 15,597 shares for $109,179, at an intra-day high of $7 per share. The cost basis of those shares to him was $5.15.

On Friday 23 September 2005, heavy selling of Corcept stock occurred (871,700 shares). This volume was 35 standard deviations above the mean of the previous 10 trading days. On the following Monday, Corcept announced that a widely publicized study of mifepristone for Alzheimer disease was being halted prematurely for lack of progress. The company also announced slower than expected enrollment in a Phase III study of psychotic depression, for which they projected delayed announcement of results. Over the next month the stock price declined 16%.

These episodes of concentrated stock movement represent coincidences that remain to be explained. Was the August 2005 upgrade and selling spike in which Dr. Schatzberg participated a case of “pump and dump”? Was the September 2005 selling spike ahead of bad news a case of insider trading? Who did all that selling, and how did they know?

The questions just keep coming.

IMPEACHMENT: IT’S ABOUT THE INSTITUTION, NOT THE PERSON

IMPEACHMENT: IT’S ABOUT THE INSTITUTION, NOT THE PERSON

The impeachment trial of Judge G. Thomas Porteous of Louisiana this week was a lesson in civic ethics. The lessons of the Porteous trial apply to academic medical centers, professional medical societies, medical journals, and granting agencies like NIH.

The Porteous trial is a straightforward case of bribes, kickbacks and corruption involving a Federal judge. The most enlightening arguments came from prosecutor Rep. Adam Schiff, D-California, laying out the case for impeachment in the Senate. He gave a lucid presentation of the logic and the historical origins of the impeachment process. The key points are these: impeachment serves to protect the dignity, honor, and credibility of the office more than to punish the wayward office holder; and impeachment is a constitutionally sanctioned way to clean the Augean stables without necessarily having to prove criminal liability. It is sufficient to demonstrate that the bad actors have brought disgrace on their offices.

What this means for us in medicine is that legalistic charges and defenses are not the right way to go in exposing and ejecting bad actors from our field. In the highly publicized cases of ethical compromise over the past few years, our group disapproval, when there was any at all, generally has run on two parallel tracks. The first is legalistic, and it favors the bad actors, who flaunt their constitutional protections with the taunt, prove it. The second ground of disapproval is esthetic, based on the tackiness of the bad actors’ behaviors – regardless of technical legalities, what they do is an affront and an insult to professional standards and mores. When we look at how recent incidents in medicine actually played out, however, we see a disconnect. The bad actors have narrowed the debate to the first ground of disapproval, while forcing the second off limits. In this strategy, they have received conscious or unconscious assistance from the professional establishment. The focus has been on legal technicalities involving the bad actors rather on preserving the dignity and credibility of high offices in academic medicine.

For instance, when Charles Nemeroff was exposed by Senator Grassley for conflict of interest in his NIH grants, he came up with the contrived legalistic defense that his unreported payments from GlaxoSmithKline were for ‘CME-like’ presentations, and thus somehow exempt from disclosure. Nemeroff’s obfuscations finally collapsed of their own weight and Emory University took decisive action against him, even though they had sufficient evidence dating back at least 4-5 years. In the end, Emory had to go through the wringer to discipline Nemeroff, and the institution suffered grave damage to its reputation for a number of years as the price of delay.

For instance, when Thomas Insel, the Director of NIMH, assured Pascal Goldschmidt, Dean of the School of Medicine at the University of Miami, that Nemeroff was absolutely in good standing for applying for new NIH grants if he left Emory for Miami, despite a 2-year ban at Emory, he hewed to the letter of the law while disregarding its spirit in order to help his friend. Moreover, when Insel appointed Nemeroff to two new NIH Research Review Committees, he established beyond any doubt that he was intent on trying to help Nemeroff get back into circulation, and that he failed to grasp the gravity of the dishonor that Nemeroff inflicted on the field. This obtuseness on Insel’s part damaged the credibility and reputation of NIMH. To his credit, NIH director Francis Collins finally ‘got it’ and forced a review of the NIH ethics rules that had been entrusted to Insel.

For instance, when Pascal Goldschmidt, Dean of the School of Medicine at the University of Miami, claimed he had done due diligence in his recruitment of Nemeroff as chair of his psychiatry department in 2009, he focused on the legalistic aspects of Emory’s review of Nemeroff, while failing to understand the degree of negative publicity associated with Nemeroff’s name. He ended up hiring someone who is an object of ridicule, and he in turn is ridiculed by association.

For instance, when Stanford University learned of Alan Schatzberg’s boundary violations vis a vis his NIH-funded projects and his personal corporation, they first pushed back on legalistic technical grounds. Only later did the Stanford administration get the message by removing Schatzberg from his Principal Investigator role with NIH grants, and eventually appointing a new chair of psychiatry. Meanwhile, the public image of Stanford suffered.

For instance, when the American Psychiatric Association was warned that Alan Schatzberg was a problematic candidate for election as President of the association on account of his history of ethical compromise, they went ahead anyway and they have since had opportunity to regret that decision. Here again, the professional society appears to have lost sight of the ethical forest for the legal trees. The credibility and reputation of the APA have suffered because of the taint associated with Schatzberg’s presidency.

For instance, when the New York Times recently exposed the ghostwriting associated with the 1999 textbook of Charles Nemeroff and Alan Schatzberg, the so-called authors responded with typical legalistic defenses. They and the University of Miami and the American Psychiatric Association Press (the publisher) again lost sight of the ethical forest for the legal trees. This stereotyped, public relations driven response ignores the visceral and esthetic distaste most observers felt on learning about the collusion between the ‘authors,’ the professional writing company and the sponsoring pharmaceutical corporation. Even the defense that it occurred a long time ago fails. In the Porteous trial, the prosecution established that dishonorable events in an officer’s past are grounds for impeachment, whether or not they also occurred during the person’s time in office.

For instance, when Harvard Medical School planned a new CME program on psychopharmacology in mid-2011, they engaged a number of compromised academic speakers, including Nemeroff and Schatzberg. What the hell was Harvard thinking? I told the Course Director, Carl Salzman, that this amounts to pandering. He replied defensively that Nemeroff and Schatzberg are well regarded speakers and that he would ensure that they gave unbiased presentations. That’s not the point. The point is that they have done serious damage to our field, and for Harvard Medical School to give them top billing amounts to denial of the elephant in the living room. It’s collusion in service of their public rehabilitation. I told Dr. Salzman that his logic amounts to compartmentalized thinking. I might have added that Adolf Hitler gave a lot of great speeches that received rave reviews and that compartmentalized thinking was widespread in the nation of Germany between 1928 and 1945. Meanwhile, Harvard Medical School gets a black eye through its association with these compromised individuals. So do the other speakers who will be on the panel. Who needs this kind of taint? Dr. Salzman can defend Nemeroff and Schatzberg all he wants on specious legalistic grounds, but who cares? Harvard Medical School could use some moral clarity.

So, we come back to the impeachment trial of Judge Porteous. Impeachment protects the institution. When sleazebags get into positions of authority and trust they need to be dumped, and our professional and academic institutions need to have enough spine to dump them. At the very least, we don’t need to tolerate institutions like Harvard Medical School pandering to compromised academic bad actors. For shame.

INSTITUTE of MEDICINE REPORT on CONFLICT of INTEREST

INSTITUTE of MEDICINE REPORT on CONFLICT of INTEREST

Today we saw a new marker laid down in the arena called Conflict of Interest (COI). The Institute of Medicine of the National Academy of Sciences issued a report of its Committee on Conflict of Interest in Medical Research, Education and Practice. The report is comprehensive, even exhaustive, running to 353 pages. Gardner Harris in the New York Times today calls it “scolding,” “stinging,” and “damning.” The recommendations go well beyond any proposed in the recent past by medical schools or by other professional organizations. The NYT quoted David Rothman, president of the Institute on Medicine as a Profession at Columbia University: “With the I.O.M.’s endorsement, issues that were once controversial now are indisputable. Conflicts of interest in medicine are no longer acceptable.”

It will take some time for the field to digest the scope of the IOM recommendations. It will take even longer for the new standards to be implemented. For now, I offer just a few observations.

First, if the IOM hopes for maximum credibility then it might ought want to do some housecleaning. A few years ago I fired a shot across the bow of the IOM concerning COI. [Can the Institute of Medicine Review the FDA? Nature Medicine 11, 369 (1 April 2005) doi:10.1038/nm0405-369] Nothing much changed, and in the following years, national scandals erupted involving several of the issues I had highlighted. Prominent IOM members, who were well known to be poster boys for COI, were exposed by Senator Charles Grassley (R-Iowa). Their embarrassing behaviors included incomplete financial disclosures and noncompliance with NIH policy on financial conflict of interest. The exposés included Emory’s Charles Nemeroff and Stanford’s Alan Schatzberg. In both cases, administrative rearrangements have now been implemented. The case of Dr. Nemeroff has been referred by Senator Grassley to the Inspector General of the Department of Health and Human Services. It is perhaps no accident that Dean Claudia Adkison of Emory and Dean Philip Pizzo of Stanford were included as external reviewers of the draft IOM report. Their insights would have been invaluable.

Another ongoing embarrassment for the IOM is Lester Crawford. He was the FDA Commissioner who resigned abruptly in 2005 and later pleaded guilty to criminal conflict of interest. He had been charged with falsely reporting information about his stock holdings in companies he was in charge of regulating. He received a sentence of three years of supervised probation and a fine of about $90,000. He is now senior counsel with a health care lobbying firm in Washington, DC. The Institute of Medicine does not help its image by continuing the membership of such a compromised individual.

As the Emory-Nemeroff and Stanford-Schatzberg cases unfolded it appeared that the respective institutions had themselves contributed to the problems, either through inaction or through studiously nontransparent procedures on disclosure. Stanford, for instance, apparently did not require faculty members to report the proceeds of stock sales, and when challenged the university invoked on-line financial reporting services and SEC filings as a sufficient substitute. Not surprisingly, because Stanford didn’t know about Dr. Schatzberg’s realized gain of some $109,000 from sale of founder’s stock in his biotech start-up company, Corcept Therapeutics, this information was not reported to NIH.

Recommendation 4.1 One of the IOM’s recommendations applies particularly to the Stanford-Schatzberg case. Recommendation 4.1 addresses the boundary between academia and commerce in the case of research involving human subjects. Here is the specific language:

“Academic medical centers and other research institutions should establish a policy that individuals generally may not conduct research with human participants if they have a significant financial interest in an existing or potential product or a company that could be affected by the outcome of the research. Exceptions to the policy should be made public and should be permitted only if the conflict of interest committee (a) determines that an individual’s participation is essential for the conduct of the research and (b) establishes an effective mechanism for managing the conflict and protecting the integrity of the research…” (page S-14).

Last year I posted several times about this issue in the Stanford-Schatzberg case. It is gratifying now to see the IOM affirm the importance of the boundary. The activities declared off-limits by the IOM include not only “recruiting subjects; obtaining informed consent; assessing the clinical end points;” but also “analyzing data; or writing the results, conclusions, and abstracts for publications reporting the findings of the study.” (page 4-17). In Stanford’s earlier plan for managing the conflict and protecting the integrity of the research, Dr. Schatzberg was free to engage in the latter group of activities. Indeed, his hands were all over the project when it came to responding to scientific critiques, managing the climate of professional opinion, attacking and threatening critics, promoting his company’s interest through review articles and press releases, slipping unpublished and non-peer-reviewed commercial data into academic reviews, and generally conducting commercially slanted public relations through academic outlets.

When Stanford adopts the IOM recommendations, such activities will be blocked. As I stated last year, “Review articles that assess a field and synthesize data form a crucial part of science that has to be off-limits to Dr. Schatzberg just as much as assessing patients in one of his clinical trials would be.”

We should congratulate the IOM committee members for their work, and we hope to see the field embrace their recommendations.

Bernard Carroll.

UPDATE 04-30-2009: The link provided earlier for the IOM report document is no longer operative. Here is where to go now for a copy of the report. This time it will cost you.

http://www.nap.edu/catalog.php?record_id=12598

WHO YOU GONNA BELIEVE?

WHO YOU GONNA BELIEVE?

Ghostwriting Charges and Stonewalling at the American Psychiatric Association

The American Psychiatric Association came under a searchlight this past December over allegations of ghostwriting. The story originated with a public letter from Project on Government Oversight (POGO) to the Director of NIH, and it was picked up by Duff Wilson writing in the New York Times. The book was Recognition and Treatment of Psychiatric Disorders: A Psychopharmacology Handbook for Primary Care. The named authors were Charles Nemeroff, now chairman of psychiatry at the University of Miami, and Alan Schatzberg, formerly chairman of psychiatry at Stanford University. Both are well known for ethical controversy – see here and here. Soon, these allegations were being dissected in the blogosphere, with stellar contributions from Daniel Carlat, 1boringoldman, Ed Silverman, and Alison Bass.

The APA and its publishing arm, known as American Psychiatric Press, Inc. or APPI, came to the defense of the two prominent academic authors over the ghostwriting charge. In particular, an APA employee named Mark Moran authored a denial of the charge in the January 2011 issue of the APA news magazine, Psychiatric News. As the controversy played out, letters from attorneys demanded retractions, and partial qualifications of the original story appeared in the New York Times and on the POGO weblog. There was never any doubt that the heavy lifting was done by a pair of professional writers employed by a medical communications company under a financial grant from a drug company. Nemeroff defended his role by averring that he ‘scrutinized’ the work product of the professional writers. Threatening letters from lawyers for Nemeroff and Schatzberg were publicized, and the APA weighed in.

The coup de grâce was administered by blogger Daniel Carlat’s withering review of the book’s artful construction to highlight the use of the sponsoring company’s antidepressant and anti-anxiety drug in primary care, while muting important information about the drug’s liabilities. Nevertheless, the APA held to its legalistic stance in defense of the ‘authors.’ This behavior is counterproductive for professional medical organizations, as I have discussed before, because it misses the ethical forest for the legal trees.

Now comes the good part. In response to the piece by Mark Moran in Psychiatric News, Leemon McHenry prevailed on Robert Rubin and myself to write with him to the magazine’s editors. Leemon is a faculty member in the Department of Philosophy at California State University, Northridge. He also has experience evaluating legal documents arising in litigation over antidepressant drugs. Robert Rubin has partnered with me in outing several notable ethics compromises involving Nemeroff and Schatzberg, going back as far as 2002, though we always call ourselves equal opportunity critics.

Our letter sent in late January to Dr. Carolyn Robinowitz, the Interim Editor of Psychiatric News, has been posted today on the POGO site. In our letter, we challenged much of Mr. Moran’s defense, and we called attention to what WASN’T in the public domain, despite all the claims and counterclaims. Essentially, the partial qualifications of the original reports that appeared in The New York Times and in the letter to NIH from POGO resulted from the inconclusiveness of some of the documents. We called on the APA to come clean with the release of all relevant materials, in the interest of transparency.

For instance, what WASN’T known were the specifics of the contract involving the corporation, the (ahem) authors, the publisher (APPI), and the medical communications company. Or the money flow to the ‘authors’ from the contract in addition to their royalties. Or the legal release form transferring ownership of the work product to the ‘authors’ and APPI. Or the corporation’s planned marketing activities, given that the corporation ordered 10,000 copies of the book. Or the correspondence among all parties that might reveal who actually did what.

Leemon McHenry’s perspective is that this hidden layer of documents may well be available if they could be unsealed in pending litigation. Naturally, corporations and their attorneys strive to keep the information hidden. But our general point is that the APA has a different duty – which is to transparency rather than to stonewalling. Did the APA do that? Sadly, no, they did not. Here is the curt reply from the Executive Editor Catherine Brown denying publication of our letter after a delay of almost 8 weeks. Now that’s what I call stonewalling.

Harvard Psychiatry Fails Again

HARVARD PSYCHIATRY FAILS AGAIN

About a year ago I remarked upon the ethical tone deafness that characterizes Harvard psychiatry. It is bad enough that Harvard-MGH is the home of Joseph Biederman, MD, with whom Senator Grassley had so much fun a while back. Biederman is still in the news. It is also the home of Andrew Nierenberg, MD, who was rash enough to take on Marcia Angell in the New York Review over her well founded criticisms of the hyping and misuse of psychiatric drugs. In response, Dr. Angell handed Dr. Nierenberg his head.

Biederman and Nierenberg are not the only ones. When I called one of the senior Harvard professors, Carl Salzman, MD, to task for signing up a pair of compromised key opinion leaders as speakers in his annual Psychopharmacology Master Class last spring, I hoped the ensuing negative publicity would persuade him to go in a different direction next time.

No such luck! Today I saw the flyer for the 2012 Harvard Psychopharmacology Master Class. The list of speakers is virtually unchanged from a year ago. There is Charles Nemeroff. There is Alan Schatzberg. Both were outed by Senator Grassley’s investigation in 2008, and both were subjected to major administrative sanctions, by Emory University and by Stanford University. Other people now occupy the departmental leadership chairs they held in 2008. There also is a group of other key opinion leaders who appear content to endure the taint of sharing the podium with the compromised Nemeroff and the compromised Schatzberg. What are they thinking?

For that matter, what is the course director Carl Salzman thinking? A year back he said Nemeroff and Schatzberg would give great talks and that he would ensure they were objective and impartial. That’s not the point. The point is that they brought dishonor on our field, and for Harvard Medical School to give them this platform amounts to compartmentalizing information in service of their public rehabilitation. To repeat what I said a year ago, Adolph Hitler also gave a lot of speeches that received rave reviews, and compartmentalized information was widespread in the nation of Germany between 1928 and 1945. The best one can say about the upcoming course is that Biederman and Nierenberg are not on the program.

The Augean stables of psychiatry, at Harvard and nationwide, will not be flushed clean by the Carl Salzmans of our field, quibbling over legal technicalities while failing to see the ethical elephant in the living room.

For how long will the grownups at Harvard Medical School allow this farce to continue?

DR. PANGLOSS AS NIH INSTITUTE DIRECTOR

DR. PANGLOSS AS NIH INSTITUTE DIRECTOR

JAMA is out today with a Commentary by Dr. Thomas Insel, Director of the National Institute of Mental Health. Using indirection, Dr. Insel has risen to the defense of seven academic psychiatrists on whom an ethical searchlight has been trained for the past several years by Senator Grassley and others. With ludicrous optimism and a series of straw man discussions, Dr. Insel makes the case that things are not really as bad as they seemed to be or, if they were, then other specialty physicians were doing much the same things. Dr. Insel needs to recalibrate his ethical compass.

Why is an NIH Institute Director issuing this apologia for the corruption of academic psychiatry? Does he not have better things to do, such as ensuring that longstanding NIH regulations on conflict of interest are enforced? Why does an NIH Institute Director presume to speak for academic psychiatry? Where are the leaders of the major professional and scientific organizations like the American Psychiatric Association, the American College of Psychiatrists, the American College of Neuropsychopharmacology, and the Society of Biological Psychiatry? Why are they not stepping up publicly to the plate? Perhaps they are confounded by the awkward fact that some of the seven individuals are current and past presidents of these very organizations. Even the Institute of Medicine of the National Academy of Sciences has not sanctioned those of the seven who are Institute members.

Why is an NIH Institute Director downplaying the gravity of the ethical controversies surrounding these compromised individuals like Charles Nemeroff at Emory (now at Miami), and Alan Schatzberg at Stanford? To hear Dr. Insel tell it, all they did was fail to disclose income from pharmaceutical companies. That is not the half of it. Readers can look here and here for much more detail on the activities of Nemeroff and Schatzberg. If Dr. Insel chose to remain ignorant of or to overlook the history of false claims on behalf of pharmaceutical corporations or the concealment of consulting relationships or the complaisance with ghostwriting or the patently misleading “educational” presentations or the cashing in through stock sales or the editorial self dealing, then Dr. Insel’s fitness to serve as an NIH Institute Director needs to be reviewed.

Surely Dr. Insel knows that Nemeroff and the others worked mainly with the marketing personnel within pharmaceutical companies. Nemeroff’s staggering schedule of promotional talks for GlaxoSmithKline, released by Senator Grassley, is testament to that. So is Nemeroff’s record of priming the pump for himself with GSK by giving the corporation unpublished research data from NIMH-funded projects at Emory. In turn, GSK and its medical education communications company, Scientific Therapeutics Information, Inc., incorporated Nemeroff’s privileged material in the training manual for PsychNet – a speaker program designed to build advocacy for GSK’s antidepressant drug Paxil. These issues go well beyond just failing to report income. They signify the corruption of academic psychiatry. Doesn’t Dr. Insel understand that?

In his Commentary, Dr. Insel reported no financial disclosures. This is a good example of the problem that Dr. Insel doesn’t see. Many readers will interpret this Commentary from the Director of NIMH as the opening move in the attempted rehabilitation of Charles Nemeroff by his friends and cronies. Though Dr. Insel spoke in platitudes about the need for transparency as a solution, the spirit of transparency did not move him to disclose that Nemeroff is his former boss at Emory; that Nemeroff found a position for him when Insel was departing the intramural research program at NIMH; that Nemeroff lobbied for Insel’s appointment as NIMH Director; and that Insel appointed Nemeroff as an advisor soon after he moved to NIMH. These are pertinent conflicts of interest that readers of JAMA deserve to know about. Quis custodiet ipsos custodes?

Maybe Dr. Insel should stick to his knitting and resist the impulse to speak for academic psychiatry as a whole. A good place for him to start looking hard would be at the productivity and accounting of the once vaunted Emory-GSK-NIMH Collaborative Mood Disorders Initiative (Principal Investigator Charles B. Nemeroff; 5U19MH069056). One never knows what one will find when the rocks are turned over.

Widespread Conflicts of Interest at Stanford: the Dean Responds

In an a commentary fo the San Jose Mercury News, Dr Philip A Pizzo, the Dean of the Stanford University School of Medicine responded to the series of articles in that newspaper documenting widespread conflicts of interest at the Medical School, which we posted about here and here. Some key quotes:

What would be the cost to the health of the American public if such ties between academia and industry were severed?

It should be noted that the federal government has explicitly promoted these ties since 1980, when Congress enacted the Bayh-Dole act, which authorized and encouraged universities to hold ownership of inventions made under federal funding. In fact this law mandates universities and private industry to work together to bring the fruits of university research to the public. This process has resulted in many medical innovations and advances that have improved the lives of millions of Americans.

There are now some 1,000 therapies and technologies that are based on university-licensed discoveries.

Of course, collaboration between university researchers and private companies carries with it the potential for conflicts of interest. The July 9 article describes one way Stanford addresses this: by requiring faculty members to disclose potential conflicts, regardless of the dollar amount of the financial interest.

But disclosure is far from the only strategy that the Stanford School of Medicine uses to protect the public's interest. When we identify a significant conflict, we take steps to eliminate, mitigate or manage it. These steps include modifying the research plan, disclosing the conflict to the public, disqualifying a faculty member from participating in all or a portion of a research project and in some cases requiring the faculty member to sever a relationship with industry.

As for the July 10 article, it is important to point out that Dr. Alan F. Schatzberg's research over the past 25 years has been consistently subject to rigorous peer review by scientific leaders at the National Institutes of Health and throughout the nation. His research findings have been published in highly respected peer-reviewed medical and scientific journals.

It is misleading to air criticism of his pilot studies for lack of statistical significance when, in fact, the studies were exploratory and not designed to show statistical significance in the first place. More important, and above all, through his research and care of patients, Dr. Schatzberg is a man devoted to alleviating the pain and suffering of those who face the challenge of the most severe and chronic forms of depression.

Dr Pizzo's response did not seem to address the points made in our previous posts about the conflicts at Stanford. (Of course, he probably has not read our posts.)

It also seems important to note that criticizing conflicts of interests does not mean criticizing the general concept of industry-academic collaboration. However, there are many ways in which universities and corporations can interact that minimize such conflicts. For example, for-profits can sponsor research at universities, but need not control the design and implementation of studies, and the analysis and dissemination of their results.

However, the examples described in the San Jose Mercury News were not simply of academic researchers collaborating with industry. They included researchers and academic leaders who owned substantial numbers of company stock options, who had corporate administrative titles, or who sat on corporate boards while doing research on the companies' products, or as full-time academics expressing opinions on topics relevant to the companies' products. It is not clear why university researchers need to get stock options, administrative positions, or board memberships from corporations in order to work collaboratively with them.

Furthermore, how can an academic be "full-time" while working for industry in an administrative position, or getting the sort of incentives that corporations usually only give to top management and key employees? At a minimum, a person in such a situation should acknowledge being only a part-time academic.

Finally, an academic who also works for industry ought to make completely transparent what masters he or she serves when expressing opinions about topics relevant to the company's product or service. Such opinions may be regarded differently than those from true full-time academics. But that's life.

However, what sort of trust is inspired when an author of scientific articles about a drug turns out to be not just a full-time university professor with some "financial interest" in the company that makes the drug, but the Chairman of the Board of the company?

INSEL and NEMEROFF - WHAT SANCTIONS?

INSEL and NEMEROFF – WHAT SANCTIONS?

Thomas Insel, Director of NIMH, has another posting in his own defense on his official blog today. He has been widely criticized lately for the appearance of cronyism in his relationship with Charles Nemeroff. For the past three months, Insel has been trying to put some distance between himself and Nemeroff, but the public isn’t buying it. I have called his statements disingenuous here and here. Dr. Insel’s statements today are equally disingenuous. Negative reactions are already appearing from those familiar with Nemeroff’s history.

There is no argument that Nemeroff was instrumental in Insel’s move to Emory in 1994, that Nemeroff was Insel’s department chairman at Emory, that Nemeroff helped Insel again when Insel’s initial term as director of the Yerkes laboratory at Emory was not renewed in 1999, or that Nemeroff lobbied for Insel’s appointment as NIMH Director in 2002. There is no argument that Insel and Nemeroff have given glowing public recommendations of each other, or that they have a record of cozy personal communications. There is no doubt that Pascal Goldschmidt at Miami sought and received a recommendation from Insel before hiring Nemeroff last year or that Insel went out of his way to put a personal gloss on the official NIH position regarding Nemeroff’s eligibility for grant funding if he left Emory. These are matters about which Dr. Insel prevaricates today in his blog.

Continuing his prevarication, Dr. Insel today also avoids confronting the issue of Nemeroff’s continuing service on NIMH review committees under Insel’s watch during the period that he was under sanction by Emory University, and banned from participating in NIH grants – before he relocated to Miami. Nemeroff’s curriculum vitae on the U Miami website states that he is a member of the NIMH Review Group, Interventions Committee for Adult Mood and Anxiety Disorders (ITAV), 7/1/2006 - 6/30/2010. This means Insel allowed Nemeroff to continue in that peer review role even though he was banned by Emory from association with NIH grants. The question is why? And what does that tell us about Insel's judgement?

It gets worse. During the period that Nemeroff was at Emory and under sanction vis à vis NIH grants, he continued to function as operational director of a NIMH-funded program administered by the American Psychiatric Association (APA). It is inconceivable that Insel was not aware of this arrangement. The APA program is known as Research Colloquium for Junior Investigators, and it is funded through NIMH project # 5R13MH064074-10. For the past few years Nemeroff, as Chair of the APA Committee on Research Training, has directed this program. The nominal Principal Investigator is Darrel Regier, who is the Executive Director of the American Psychiatric Institute for Research and Education (APIRE). At the session in New Orleans during the annual APA meeting last month, one of the featured speakers was Bruce Cuthbert, PhD, one of Insel’s principal lieutenants. In God’s name, why is the APA fronting the compromised Nemeroff as a role model to junior investigators, and why does NIMH/Insel allow this unsavory arrangement to continue? Could it be that Nemeroff’s crony Alan Schatzberg, the outgoing president of the APA, ran interference for his friend? And what will the new APA president Carol A. Bernstein do about it?

And then there is the issue of Nemeroff’s appointment to two new NIMH review committees just recently. Dr. Insel prevaricates again about his awareness or approval of those actions. As reported by Paul Basken in the Chronicle of Higher Education, “An NIH spokesman, John T. Burklow, answering written questions about the matter, confirmed Dr. Nemeroff's full eligibility for agency activities and said he will begin serving this coming week on two scientific panels that review NIH grant applications.” Here again, Dr. Insel seems to be trying to help his crony Nemeroff to get back into circulation after his fall from grace at Emory.

Emory University went through the wringer to discipline Nemeroff, at long last, in 2008. The actions of Insel in running interference for Nemeroff’s rehabilitation must leave Emory perplexed. Are Dr. Insel’s statements today disingenuous? You bet. Isn’t it time for the adults at NIH to step in and end this farce?

DOES AMERICAN PSYCHIATRY MATTER?

DOES AMERICAN PSYCHIATRY MATTER?

The blogmeister of 1boringoldman.com has done it again. A semi-retired psychiatrist in rural Georgia, he has done more than anyone to document the follies and the ethical challenges of contemporary American psychiatry. His site is required reading for all who care about behavioral health issues.

In his latest posting he compared the domain of American psychiatry to Yugoslavia. Cast Melvin Sabshin as Marshal Tito. Sabshin was the medical director of the American Psychiatric Association in the late 1970s, the period leading up to DSM-III. Tito and Sabshin each strong-armed a confederation of sorts but failed to deal with the conflicts beneath the surface. Both leaders were faced with the prospect of their domains disintegrating – Tito’s at the hands of Moscow and Sabshin’s at the hands of insurance companies. Both persuaded wary stakeholders to sign on to a compromise, for want of anything better and fearing a worse outcome.

The domain of psychiatry hasn’t yet reached the stage of ethnic cleansing and genocide that we saw in Yugoslavia after Tito’s death, but it is well on the way. One only has to look at the vicious response of the American Psychiatric Association leaders to Allen Frances and other critics of DSM-5. The APA president in 2009, Alan Schatzberg from Stanford, went out of his way to smear Dr. Frances and Robert Spitzer, the architects of DSM-IV and DSM-III because he had no credible scientific response to their criticisms of the directions DSM-5 is taking. He was joined in this low act by David Kupfer and Darrel Regier, who are directing the DSM-5 effort. Where is the comity, Comrades? Where are the shared values? Why is the APA holed up in a bunker?

Then we have the unsavory sight of the APA lawyers threatening a blogfrauchen in the U.K. with a SLAPP lawsuit for alleged infringement on the APA’s intellectual property – as though the APA owns psychiatric classification! Talk about chutzpah. So now the confederation Sabshin cobbled together is breaking up and the stakeholders are starting to go their separate ways – psychologists, counselors, social workers, patient advocacy groups, even many psychiatrists. Christopher Lane in Psychology Today has said American psychiatry is facing “Civil War” over its diagnostic manual. Even an international psychiatric journal like British Journal of Psychiatry is distancing itself from DSM-5 and there is talk of abandoning DSM-5 for the next ICD classification.

Why is American psychiatry self destructing? Because the grand bargain forged in 1980 with DSM-III was a sham from the get-go and the promised benefits of diagnostic reliability have not materialized. They knew all along that reliability was a poor substitute for validity, but they settled for half a loaf. That compromise led us into the epistemologic quagmire of today, where there is no solid ground for clinical decisions or clinical research progress or drug development. A stunning absence from the DSMs to date is any statement about treatment. That compromise also led us to diagnostic inflation, which Pharma embraced. Pharma quickly filled the vacuum with experimercials that pretended to be real clinical science, and in the process diverted precious clinical research infrastructure away from genuinely important questions. Just look at the clinical trials er, experimercials, mill operating out of Massachusetts General Hospital at Harvard University.

What lies ahead? Stakeholders are going to vote with their feet. DSM-5 is likely to be a footnote in the history of psychiatric classification. The APA will become even less relevant than it is today, much like the American Medical Association, which now commands the loyalty of maybe 30% of U.S. physicians. Mel Sabshin will turn in his grave, the APA will lose revenue, ICD-11 will become the dominant classification of psychiatric disorders, and the quagmire will continue until a new synthesis arises from the ashes. If Yugoslavia is any kind of model, don’t hold your breath.

Quis Custodiet Ipsos Custodes? Redux

Revised HHS Rules for Conflict of Interest Fall Short

This morning NIH Director Dr. Francis Collins announced revisions to the existing 1995 regulations on objectivity in research that is funded by the Public Health Service. The focus is on significant financial interests (SFI) and on financial conflicts of interest (FCOI). The regulations illustrate the 3-way dance involving academic institutions (the grantees), NIH (the grantor) and academic scientists (the investigators). Thanks to Senator Grassley (R-Iowa) and his investigator Paul Thacker, headlined revelations in recent years about unacceptable management of FCOI at places like Stanford (Alan Schatzberg), Emory (Charles Nemeroff) and Harvard (Joseph Biederman) forced these revisions of the NIH regulations.

The general initial reaction to the new rules has been critical – here and here, for instance. Many stakeholders had urged the NIH to require that institutions make the disclosed FCOI of their investigators available on a public website. Dr. Collins had intimated that we could expect to see this change, so there is consternation that it somehow became derailed by institutional lobbying in recent months. The stated concern was that institutions would feel burdened by the need to maintain these data bases. Instead, if citizens wish to inquire about FCOI involving PHS-derived research funding, they will need to write to the institution, which is obliged to respond within 5 days. That’s not exactly user friendly. POGO today made the smart suggestion that the data could easily be attached to information about awarded funds on the NIH RePORTER website, that already exists.

A second failing is that the revised regulations do not close the regulatory loophole through which Charles Nemeroff strolled when he moved from Emory to the University of Miami. We covered that incident several times on this blog last year. Though Nemeroff was under a 2-year sanction and banned from participating in NIH-funded research at Emory, his friend Thomas Insel, Director of NIMH, assured the dean of the medical school at Miami that Nemeroff was in good standing to apply for NIH funding when he moved from Emory. To underline the point, Insel displayed the bad judgment of appointing Nemeroff to 2 new NIMH review committees.

Do today’s revised regulations prevent a repeat of this administrative travesty? No, they don’t. There is some mention of ensuring oversight if a sanctioned investigator wishes to transfer a grant to a new institution, but nothing to prevent the Nemeroff-Insel dance from being repeated. Here is the relevant section of today’s announcement (page 89):

We did, however, agree with one respondent that it would be helpful to clarify, in the grants context in particular, that institutional sanctions against an Investigator can travel with the Investigator upon his or her transfer to another Institution. Specifically, we have revised 42 CFR 50.606, paragraph (a), as follows: “If the failure of an Investigator to comply with an Institution’s financial conflicts of interest policy or a financial conflict of interest management plan appears to have biased the design, conduct, or reporting of the PHS-funded research, the Institution shall promptly notify the PHS Awarding Component of the corrective action taken or to be taken. The PHS Awarding Component will consider the situation and, as necessary, take appropriate action, or refer the matter to the Institution for further action, which may include directions to the Institution on how to maintain appropriate objectivity in the PHS-funded research project. The PHS may, for example, require Institutions employing such an Investigator to enforce any applicable corrective actions prior to a PHS award or when the transfer of a PHS grant(s) involves such an Investigator.”

This revision is intended to reference the range of options for the PHS Awarding Component to consider, depending on the specific circumstances at issue. For example, PHS may decide to initiate government-wide suspension or debarment of the Investigator under 2 CFR Part 376; or to use enforcement measures under 45 CFR 74.62, e.g., perhaps to make the approval of a transfer contingent upon the former Institution’s disclosure of the corrective action- including the specific sanctions against the Investigator- to the new Institution; and/or to use special award conditions under 45 CFR 74.14, e.g., perhaps to make the new Institution agree to take the same or similar action against that Investigator or explain to the PHS Awarding Component in writing why such action was not taken and what alternative measures will be used to ensure compliance.

What’s wrong here? Everything is optional; everything is discretionary; everything is contextual – that is a formula for NIH and the academic institutions to just look the other way. And if a Nemeroff decides just to relocate without transferring a grant then he is free to start reapplying again right away. Miami would not be required to continue applying the Emory sanction banning him for 2 years from involvement in federal grants. The PHS Awarding Component (NIMH in this case) may or may not get involved, or it may pass the buck to the new institution. So what has changed? If it is left up to compromised federal bureaucrats like Thomas Insel, and institutional administrators like Pascal Goldschmidt at Miami, then nothing has changed. It's business as usual, folks.

Dr. Collins, you have not done what you set out to do. Too bad.