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.
Showing posts with label mifepristone. Show all posts
Showing posts with label mifepristone. Show all posts
Thursday, August 14, 2008
Thursday, August 07, 2008
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.
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.
Friday, July 25, 2008
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.
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.
Sunday, June 29, 2008
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.
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.
Monday, November 20, 2006
IS THERE A BASIC SCIENTIST ON THE BENCH?
One of the innovations in stealth infomercials that pharma has developed is the basic science play. Here’s how it works, illustrated in masterly style by the good people at Corcept Therapeutics.
Since 2001, Corcept has been touting a drug called mifepristone (that’s right, RU486) for treatment of patients with psychotic major depression (PMD). The drug blocks cortisol receptors, and high cortisol was theorized to be a cause of the delusions and hallucinations experienced by patients with PMD.
Corcept got fast track approval for their drug from the FDA on the somewhat specious ground that there are no FDA-approved treatments for PMD. They have published a series of small clinical trials that had negative outcomes. One tiny study (N = 5) had no statistically significant result. A second study of 30 patients had no statistical analyses whatsoever. In another study of 30 patients, the statistical analysis was incorrect. These failures did not stop the Corcept team from talking up the drug’s potential in review articles, book chapters, Continuing Medical Education programs, news reports, and press releases. In quite a few of these promotional “product placements,” the financial ties of the authors with the company were not disclosed.
All that is pretty much par for the course in the academic-industrial complex: clinical key opinion leaders were bought and paid for long ago. Now comes the basic science play. In the August 2006 issue of Journal of Neuroendocrinology, a report describes how Corcept’s drug can reverse the deleterious effect of high glucocorticoid levels on neurogenesis in the hippocampus of rats (1). This finding ties in with some inconclusive evidence that some patients with depression may have reduced hippocampal volume. So, this new basic finding is potentially a big deal for Corcept. Indeed, Corcept provided funding for the study. One fully expects that the company will highlight this new information in future statements.
Looking at the new report, one sees in the Acknowledgements that the first author was supported by Corcept. One also sees that a co-author, E. Ronald de Kloet, failed to disclose his relationship to the company: he is a member of Corcept’s scientific advisory board and, unless he has sold any, the owner of 60,000 shares of Corcept stock. One also sees that this basic science article is careful to follow the company’s marketing message and branding language on the putative efficacy of mifepristone for PMD. For instance, it states, “The glucocorticoid receptor antagonist mifepristone has been shown to rapidly and effectively ameliorate symptoms of psychotic major depression.” These basic scientists also stated, “recent clinical studies have shown that the glucocorticoid-receptor (GR) antagonist mifepristone relieves symptoms of psychotic depression after a remarkably brief treatment period of 4 or 8 days.” None of the cited studies shows anything of the sort. We then read, “… similarly to its clinical efficacy, mifepristone’s effects on adult neurogenesis are rapid and positive, and may therefore be important for its mechanism of action.”
What’s going on here? Could it be that one of Corcept’s basic science consultants has been pulled off the bench to pinch hit for the company? The usual readership of Journal of Neuroendocrinology will know nothing about the clinical trials of the drug and will accept at face value the exaggerated statements of mifepristone’s efficacy in PMD. And now the clinical spokespeople for Corcept can point to a new piece of basic science “validation” of their product. Look for it to be highlighted in the next round of book chapters, review articles in clinical journals, CME events, and press releases.
The company needs pinch hitters right now because they have recently had to announce that two large Phase III trials failed. The house of cards is collapsing: they have been informed by NASDAQ that the company is in danger of being delisted because the share price has gone from $12 at issue in April 2004 to around 80 cents today. All in all, Corcept is a case study in bad outcomes for academic entrepreneurs and their backers. Many investors have been burned. Worse, after going through around $95 million of venture capital and IPO proceeds, not to mention several million dollars of NIMH funding, they have failed to answer the original question: does mifepristone help seriously ill patients with PMD accompanied by elevated cortisol production? Now, as the company enters what may be its final spasm of activity, comes this new corruption of the basic medical science literature.
We have long known that citations of the medical literature are not holy writ, but now they are becoming advertising copy. As George Winokur, former chair of psychiatry at the University of Iowa, liked to joke, the medical literature is like the Bible: people can find in it whatever they are looking for. Some of us learned in our training that when we cite an article in one of our manuscripts, we need to actually read that article, understand its methods, and agree with its conclusions. Had the authors of this stealth infomercial in Journal of Neuroendocrinology scrutinized the clinical trials reports that they cited, even as basic scientists they would have recognized the weakness of the evidence. Thus does the corporate mandate to put lipstick on the pig vitiate even the basic medical science literature.
Reference
(1) Brief Treatment With the Glucocorticoid Receptor Antagonist Mifepristone Normalises the Corticosterone-Induced Reduction of Adult Hippocampal Neurogenesis. By: Mayer, J. L.; Klumpers, L.; Maslam, S.; de Kloet, E. R.; Joëls, M.; Lucassen, P. J.. Journal of Neuroendocrinology, Aug2006, Vol. 18 Issue 8, p629-631, 3p, 1 graph; DOI: 10.1111/j.1365-2826.2006.01455.x; (AN 21447609)
Since 2001, Corcept has been touting a drug called mifepristone (that’s right, RU486) for treatment of patients with psychotic major depression (PMD). The drug blocks cortisol receptors, and high cortisol was theorized to be a cause of the delusions and hallucinations experienced by patients with PMD.
Corcept got fast track approval for their drug from the FDA on the somewhat specious ground that there are no FDA-approved treatments for PMD. They have published a series of small clinical trials that had negative outcomes. One tiny study (N = 5) had no statistically significant result. A second study of 30 patients had no statistical analyses whatsoever. In another study of 30 patients, the statistical analysis was incorrect. These failures did not stop the Corcept team from talking up the drug’s potential in review articles, book chapters, Continuing Medical Education programs, news reports, and press releases. In quite a few of these promotional “product placements,” the financial ties of the authors with the company were not disclosed.
All that is pretty much par for the course in the academic-industrial complex: clinical key opinion leaders were bought and paid for long ago. Now comes the basic science play. In the August 2006 issue of Journal of Neuroendocrinology, a report describes how Corcept’s drug can reverse the deleterious effect of high glucocorticoid levels on neurogenesis in the hippocampus of rats (1). This finding ties in with some inconclusive evidence that some patients with depression may have reduced hippocampal volume. So, this new basic finding is potentially a big deal for Corcept. Indeed, Corcept provided funding for the study. One fully expects that the company will highlight this new information in future statements.
Looking at the new report, one sees in the Acknowledgements that the first author was supported by Corcept. One also sees that a co-author, E. Ronald de Kloet, failed to disclose his relationship to the company: he is a member of Corcept’s scientific advisory board and, unless he has sold any, the owner of 60,000 shares of Corcept stock. One also sees that this basic science article is careful to follow the company’s marketing message and branding language on the putative efficacy of mifepristone for PMD. For instance, it states, “The glucocorticoid receptor antagonist mifepristone has been shown to rapidly and effectively ameliorate symptoms of psychotic major depression.” These basic scientists also stated, “recent clinical studies have shown that the glucocorticoid-receptor (GR) antagonist mifepristone relieves symptoms of psychotic depression after a remarkably brief treatment period of 4 or 8 days.” None of the cited studies shows anything of the sort. We then read, “… similarly to its clinical efficacy, mifepristone’s effects on adult neurogenesis are rapid and positive, and may therefore be important for its mechanism of action.”
What’s going on here? Could it be that one of Corcept’s basic science consultants has been pulled off the bench to pinch hit for the company? The usual readership of Journal of Neuroendocrinology will know nothing about the clinical trials of the drug and will accept at face value the exaggerated statements of mifepristone’s efficacy in PMD. And now the clinical spokespeople for Corcept can point to a new piece of basic science “validation” of their product. Look for it to be highlighted in the next round of book chapters, review articles in clinical journals, CME events, and press releases.
The company needs pinch hitters right now because they have recently had to announce that two large Phase III trials failed. The house of cards is collapsing: they have been informed by NASDAQ that the company is in danger of being delisted because the share price has gone from $12 at issue in April 2004 to around 80 cents today. All in all, Corcept is a case study in bad outcomes for academic entrepreneurs and their backers. Many investors have been burned. Worse, after going through around $95 million of venture capital and IPO proceeds, not to mention several million dollars of NIMH funding, they have failed to answer the original question: does mifepristone help seriously ill patients with PMD accompanied by elevated cortisol production? Now, as the company enters what may be its final spasm of activity, comes this new corruption of the basic medical science literature.
We have long known that citations of the medical literature are not holy writ, but now they are becoming advertising copy. As George Winokur, former chair of psychiatry at the University of Iowa, liked to joke, the medical literature is like the Bible: people can find in it whatever they are looking for. Some of us learned in our training that when we cite an article in one of our manuscripts, we need to actually read that article, understand its methods, and agree with its conclusions. Had the authors of this stealth infomercial in Journal of Neuroendocrinology scrutinized the clinical trials reports that they cited, even as basic scientists they would have recognized the weakness of the evidence. Thus does the corporate mandate to put lipstick on the pig vitiate even the basic medical science literature.
Reference
(1) Brief Treatment With the Glucocorticoid Receptor Antagonist Mifepristone Normalises the Corticosterone-Induced Reduction of Adult Hippocampal Neurogenesis. By: Mayer, J. L.; Klumpers, L.; Maslam, S.; de Kloet, E. R.; Joëls, M.; Lucassen, P. J.. Journal of Neuroendocrinology, Aug2006, Vol. 18 Issue 8, p629-631, 3p, 1 graph; DOI: 10.1111/j.1365-2826.2006.01455.x; (AN 21447609)
Friday, July 14, 2006
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:
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?
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?
Tuesday, July 11, 2006
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:
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.
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.After the company was formed,
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.
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.After the study reported by the first paper above was performed,
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.
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.'However, some strongly criticized this study.
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.
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.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 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.
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.
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