Conflicts, Bad Science, and Corlux: Part Two

The blogosphere has been abuzz with discussion of psychiatrist Alan Schatzberg's dual roles as a tycoon and an allegedly "objective scientist."  But wait... there's more.  Schatzberg is deeply involved with Corcept Therapeutics, a company that has repeatedly found that mifepristone (Corlux/RU-486) is a dud for psychotic depression.  Yet Corcept has continually attempted to spin the results as positive, in a manner that should be obvious to anyone who passed an introductory research methods or statistics course.  Schatzberg has millions of dollars in Corcept shares and should Corcept actually turn out to possess even minimal efficacy for psychotic depression, Schatzberg stands to profit quite handsomely.  

Bernard Carroll has the next chapter in this interesting saga, dealing particularly with Stanford University's claim that Schatzberg was not involved in "managing or conducting any human subjects research" using Corlux.  Such a claim is essentially saying that because of his financial connections with Corcept, Schatzberg avoided tight involvement with the studies of the drug so that he could avoid a conflict of interest.  Dr. Carroll, however, notes that it seems very likely Schatzberg was indeed involved in Corlux research.

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.

That's just a tidbit -- there is much more to the story, and it should be read immediately at Health Care Renewal.  Keep in mind that Schatzberg is the president of the American Psychiatric Association.  You may then choose to giggle or cry -- your choice.  

Conflicts, Bad Science, and Corlux

Recently, the watchful eyes of Charles Grassley have been peering into the bank accounts of big name psychiatrists. Melissa DelBello and Joe Biederman (1, 2) from the Wonderful World of Child Bipolar were first, and now Alan Schatzberg has been hit. Schatzberg is the Chair of Psychiatry at Stanford University. He is also the President of the American Psychiatric Association. In other words, he's kind of a big deal.

Pharmalot hits the details, but the gist is that Schatzberg is deeply involved at Corcept Therapeutics, a company for which he is chair of the scientific advisory board and holds a large amount of stock. According to Grassley, he did not disclose some of his stock sale profits or the magnitude of his multimillion dollar stock holdings in the company. Additionally, Schatzberg allegedly underreported income received from other drug companies. It appears that Schatzberg was not really required to disclose some of this information, so according to my brief review of the information, it is quite possible that he has broken no rules. Now, whether the rules need to be changed is a different story. No offense to Grassley, but I was well ahead of him on part of this story, noting in April 2007 that Schatzberg had a mega-conflict of interest going with Corcept. I also noted previously that Schatzberg was on the Zyprexa bandwagon, helping to "educate" fellow physicians about the Lilly wonder drug.

The Real Problem: But amidst all this discussion of conflicts of interest, I am afraid that we are getting a bit diverted from the main problem, that of shoddy science. It is admittedly interesting noting that Schatzberg is somehow supposed to be an independent, disinterested scientist while standing to make an absolute truckload of money if his sponsored product succeeds. But it runs deeper. While Schatzberg is a bigwig at Corcept, let's review how Corcept's main product mifepristone (RU-486; yes, the abortion pill) has done.

Mifepristone (aka Corlux) is intended to work as a treatment for psychotic depression. One main problem: It doesn't relieve depressive symptoms. In multiple trials, it has failed to demonstrate antidepressant properties. The CEO of Corcept and another member of their scientific advisory board have previously tried to spin away such inconvenient data by painting negative results as positive. To give Corcept credit, their scientists are consistent spinmeisters, seemingly always able to dredge a positive from obviously negative findings. Schatzberg has been an author on a couple Corlux-related papers that were shredded by independent analysts, who found statistical problems and overly optimistic interpretations of the study results. As the senior member of the Scientific Advisory Board, I assume that Schatzberg had some input on the other study reports that also overstated the efficacy of Corlux.

Could his millions of dollars in Corcept holdings bias Schatzberg, either subconsciously or overtly? You be the judge. But remember that this is not just about conflicts of interest -- this is about science. There is hard evidence that the research on Corlux, which is tightly linked to Schatzberg, has been misinterpreted for the sake of marketing. Conflicts of interest sometimes lead to bad science, but rather than focus just on conflicts of interest, we need to dig a layer deeper and see the poor science -- the shoddy evidence that is used as the foundation for "evidence based medicine" in many cases.

Note also that David Healy has written an interesting piece on the topic of conflicts of interest and bad science, pointing out that a larger problem is lack of access to company-owned data. Think Paxil and suicide. He concludes:

If I were employed in a company marketing department I would much prefer to have the field think that all that is wrong is that a few corrupt academics fail to declare competing interests than to have the field think that company practices that restrict access to data while still claiming the moral high ground of science are the real source of the problem.

I'd love to know what American Psychiatric Association members think about this. The news had already broken about Schatzberg overstating the efficacy of Corlux before he was elected APA president. Do APA members not care that their president has a documented record of putting product promotion before scientific evidence?

4.83 Million Reasons to Be Conflicted

Corcept Therapeutics just got an infusion of cash. From the press release:

Corcept Therapeutics Incorporated (NASDAQ: CORT) today announced the completion of a private placement of 9,000,000 shares of its common stock at a price of $1.00 per share, pursuant to a definitive agreement entered into today with accredited investors. The investors are led by Paperboy Ventures LLC, who is currently a significant shareholder of Corcept. Sutter Hill Ventures, Alta Partners, LLP, venture capital firms that are currently significant shareholders in Corcept, and members of the Corcept Board of Directors, Joseph C. Cook, Jr., James A. Harper, David L. Mahoney, Alan F Schatzberg, M.D. and James N. Wilson, are also investors. In addition, investors in this financing round included Black Point Group, LLP, Vaughn Bryson and Daniel Bradbury.

Already a good short-term investment, as the stock is now at $1.21 a share. If you've read my prior writings about Corcept, you can see that I'm highly skeptical about it's main product, Corlux (mifepristone/RU-486), which is aiming to treat psychotic depression. Although the company has tried to spin negative findings as actually being positive, it's hard to see how a series of studies showing poor efficacy will lead to helping patients in any meaningful fashion. Might the latest influx of cash help out the Corcept insiders who hold a major stake in the company? Sure.

Conflicts of Interest: It appears that Dr. Alan Schatzberg bought 50,000 shares in the latest round of funding. It has been reported previously that Schatzberg has written quite positive comments about Corlux in journals and some have questioned whether his financial stake in the company has skewed his judgment on the topic. I want everyone to consider the following conundrum...

Schatzberg holds about 4.83 million shares of Corcept currently. So, if Corlux bombs a clinical trial, is he going to:
A. Immediately report the negative results in a press release
B. Move publishing the negative results in a scientific journal to the top of his to-do list
C. Spin the results in a very favorable fashion (or make sure that someone who writes the press release and/or scientific paper does so)
D. Just bury it entirely (probably not an option with such a small company that likely announces most if not all of its trials beforehand)

If I was in a position where I had such a large financial stake, I'd have a hell of a time doing A. or B. When large dollar amounts are at stake, it's not easy to say, "Hey, this product doesn't seem to work" and watch your stock holdings evaporate. This is why conflicts of interest are a problem.

Some academic researchers really are just in it for the money. I think they are a very small minority. I bet that most researchers who end up with big-time conflicts of interest start off thinking, "Hey, this could be a great new form of treatment for condition X." Then, hey, why not make some money while you're doing God's work, helping to heal people. We're an entrepreneurial society, so we tend to believe that people should be rewarded for having an enterprising spirit. Now, if the product turns out to not be so effective and/or to have some unpleasant side effects, then look at the predicament... Here's the conflict -- help people with condition X or help my own cash flow?

Or say I'm a doctor who makes some good money on the side giving "educational" speeches to fellow physicians about a drug, say, Zyprexa. When I find out that said drug is linked to numerous health problems, do I bring that up in my speeches, knowing fully that such discussion is likely going to get me canned from the speaking circuit?

The list of potential examples could go on for days.

Corcept: We'll Take Our Ball and Go Home

...because we can't afford the basketball court. Corcept, which has run a series of studies (1, 2) demonstrating poor efficacy of its drug Corlux (mifepristone/RU-486) in treating psychotic depression, has watched its chief financial officer resign (way to get off the sinking ship Fred!) recently. Corcept also stated in a press release that...

For the fourth quarter of 2006, Corcept reported a net loss of $3.9 million, or $0.16 per share, compared to a net loss of $5.2 million, or $0.23 per share, for the fourth quarter of 2005. For the full year 2006, the company reported a net loss of $24.9 million, or $1.09 per share. This compares to a net loss of $20.1 million, or $0.89 per share, for the full year 2005.As of December 31, 2006, Corcept had cash, cash equivalents and marketable securities of $9.5 million. The total cash used in the company's operating activities for the full year 2006 was $23.2 million. Commenting on Corcept's financial guidance for 2007, Fred Kurland, Corcept's Chief Financial Officer, stated, "Based on the currently planned timeline of our clinical development program and assuming that we are able to raise funds for intended operations, we expect that net cash used in 2007 will be between $10 million and $15 million. If we are not able to raise additional funds, we will not be able to continue operations beyond the second quarter of 2007."

Sounds like a plea of desperation to me. Anyone willing to sign up? I'll just get my checkbook out now. Corcept stock (incredibly) was once valued at over $10 per share, and now sits at 71 cents. I guess you could call this an extreme form of value investing (except for the company's lack of earnings). It appears that just issuing press releases and/or writing journal articles that spin their negative findings as positive is not working so well.

Corcept Spins Out

The interesting thing about Corlux (mifepristone/RU-486) is that no matter how it fares in clinical trials, it is always a winner. In the latest trial, Corlux was again not effective on the primary outcome measure, which assessed the psychotic symptoms of psychotic depression. This is not surprising, since it has generally shown mediocre results, which are then spun by the company executives/academics as evidence of treatment effectiveness. Oh, and despite this being pushed as a treatment for psychotic depression, the treatment has never yielded anything resembling efficacy for depression, which strikes me as pretty odd.

Dr. Joseph Belanoff, Corcept CEO, had the following to say about the latest trial results:

While we are disappointed that the trial did not meet the primary endpoint, we are particularly encouraged to have met the important predefined threshold concentration endpoint with statistical significance," said Joseph K. Belanoff, M.D., Corcept's Chief Executive Officer. "This study confirms our previous observation that at higher plasma levels the drug candidate is able to demonstrate desired clinical effects. In particular, those patients in Study 06 who achieved a predetermined level of 1661 nanograms of CORLUX per milliliter of plasma separated from the placebo group with statistical significance.

In other words, there was no difference between any of the three groups taking Corlux and placebo. None. So it appears that they started data dredging (e.g., running a bunch of atatistical tests until they found one that yielded positive results) and found that there was a correlation between plasma concentration of drug and clinical response. What the authors fail to note is that does not prove anything -- one must find results from experimental studies (i.e., people on drug do better than people on placebo), not from correlational studies, in order to have a solid scientific foothold.

An academic, who serves on Corcept's scientific advisory board, was also willing to make a sunny statement about the findings:

Ned H. Kalin, M.D., Hedberg Professor and Chair of the Department of Psychiatry at the University of Wisconsin, said, "The correlation between plasma levels of drug and response rates found in this trial is very exciting. The results of this study show that when psychotically depressed patients achieve a threshold concentration of CORLUX in their system, a rapid and sustained clinical response is likely. This is a strong demonstration of a drug effect in an illness that is potentially devastating and difficult to treat."

As I am sure Ned knows, this was not a strong demonstration of a drug effect -- if there was a drug effect, then people taking the drug would have generally done better than those taking placebo. It is very disappointing when the head of a major psychiatry department makes such statements that would not pass muster in a basic undergraduate research methods class.

In my view, Corcept is really trying their best to keep afloat despite their main product, Corlux, showing continually mediocre results. Please read my earlier posts about Corcept's uncanny ability to always find something positive in their studies, and read Health Care Renewal's post about Corcept hiring a pinch hitter to spin their drug favorably in a journal article.

Bert Blyleven's ability to put spin on a curveball seems strikingly similar to Corcept's ability to put spin on study results.