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.

4 comments:

pooja said...

Mifepristone is a synthetic steroid compound used as a pharmaceutical.
Mifepristone was approved for use in India in 2002.It is only available under medical supervision, not by prescription, due to adverse reactions.and there are criminal penalties for buying or selling it on the black market or over-the-counter at pharmacies.

Mari M said...

Why would Dr. Schatzberg even be considered to head the APA now? This type of hidden financial gain at the expense of the medical consumer is hypocritical. Dr. Schatzberg and the people working for him at Stanford should not be heralding his own drug's miracle cures through the stance of a "researcher," rather than as an "owner of Corcept." The public should know what Stanford claims they knew--that Dr. Schatzberg owned a $6M stake in its performance. Every time he touted Mifepristone's benefits, that was also a self-serving statement with SEC implications.

Anonymous said...

It is very tragic in this country where money just about buys everything.

Dr. Schatzberg should be placed in prison for what he has done here.

I applaud Senator Grassley for getting out the REAL truth on Dr. Schatzberg.

Anonymous said...

Oh please. The UK are doing trials too and good results in many cases so let's not jump to conclusions about the value-add of the drug for use in psychiatric conditions because a drug company is doing trials or evaluations (what so new about that or having scientists on their Board or employed by their company)


Persistent effects of mifepristone (RU-486) on cortisol levels in bipolar disorder and schizophrenia.
1: J Psychiatr Res. 2008 Oct;42(12):1037-41. Epub 2008 Feb 5.
http://www.ncbi.nlm.nih.gov/pubmed/18255098
Gallagher P, Watson S, Elizabeth Dye C, Young AH, Nicol Ferrier I.
School of Neurology, Neurobiology and Psychiatry, Newcastle University, Leazes Wing, Royal Victoria Infirmary, Newcastle Upon Tyne NE1 4LP, UK. peter.gallagher@newcastle.ac.uk

Recent pre-clinical and clinical studies have examined the potential use of anti-glucocorticoid drug augmentation - including glucocorticoid receptor (GR) antagonists - as a method of improving treatment response in severe psychiatric illness. However, the direct and persistent effects such drugs exert on the hypothalamic-pituitary-adrenal (HPA) axis are unclear. We examined afternoon cortisol levels in 39 patients (19 with bipolar disorder, 20 with schizophrenia) at baseline, following treatment with mifepristone (600mg/day for 7 days) or placebo and at +21 days. Following treatment with mifepristone (day +7) there was a significant increase in cortisol levels from baseline (mean change=60,434nmol/Lxmin, 95%CI=44,755-76,112; t=7.803, df=38, p<0.0001) which significantly decreased from this point by day +21 (mean change=-64,487nmol/Lxmin, 95%CI=-49,974 to -79,001; t=8.995, df=38, p<0.0001). Cortisol levels at day +21 were significantly lower than they were at baseline (mean change=-4054nmol/Lxmin, 95%CI=-456 to -7652; t=2.281, df=38, p=0.028). No significant changes occurred following placebo. These results provide preliminary evidence that subtle but significant reductions in HPA axis activity (measured by peripheral cortisol levels) are evident 14 days after cessation of treatment with the GR-antagonist mifepristone. This may in part underlie the putative therapeutic effects of such drugs.

PMID: 18255098 [PubMed - in process]