More Evidence for Suppression of Research: the Case of Lamictal for Depression

We recently discussed the severe challenges to evidence-based medicine presented by manipulation and suppression of clinical research to serve vested interests.  I recently (and unfortunately belatedly) came upon yet another example of suppression of research that was unfavorable to a research sponsor's vested interests, suggesting that such suppression may be more prevalent than heretofore believed. 

This example appeared in the journal Evidence-Based Mental Health [Gahemi SN. The failure to know what isn't known: negative publication bias with lamotrigine and a glimpse inside peer review.  Evidence Based Mental Health 2009; 12: 65-68.  Link here.]

The author was able to use the database of clinical trials provided by GlaxoSmithKline as part of a settlement of a suit by former New York state Attorney General Elliot Spitzer that charged that the company had suppressed information about the selective serotonin reuptake inhibitor paroxetine (Paxil).  His interest was the use of lamotrigine (Lamictal) in depression.  His main findings were:

Of the nine lamotrigine related bipolar disorder studies posted on the website (see table 1), two were positive and published supporting the FDA approved indication for delay of relapse in the long term treatment for bipolar disorder patients. A negative study in rapid cycling bipolar disorder and another in acute bipolar depression were published but both emphasised positive secondary outcomes as opposed to the negative primary outcomes. Five other negative studies involving rapid cycling bipolar disorder, acute bipolar depression and acute mania have not been published and are only available on the GSK website.

Failure to adequately publish these negative studies led to the creation of a clinical impression that lamotrigine is an 'antidepressant,' a view innocently expressed to me as recently as last week by an academic colleague. This mistaken impression occurred partly because the prophylactic benefits of lamotrigine for depressive episodes were confused with a presumed acute benefit. Partly it was due to the publication of one apparently positive study, and the non-publication of several negative studies.

The clinical relevance of the lamotrigine studies is notable: taking the negative outcomes into account, as of now, one might say that this agent is reasonably effective in maintenance treatment of bipolar disorder, particularly in prevention of depression. It is proven ineffective in acute mania, rapid cycling disorder and acute bipolar depression.

Note that Dr Ghaemi and colleagues had published a summary of the suppressed negative articles in Medscape Journal of Medicine in late 2008.  [Ghaemi SN, Shirzadi AA, Filkowski M. Publication bias and the pharmaceutical industry: the case of lamotrigine in bipolar disorder. Medscape J Med 2008; 10(9):211.  Link here.]  That earlier article also documented the group's failed attempts to discover whether negative trials of other drugs for depression had been suppressed.

Dr Ghaemi's newer made some additional important points about suppression of clinical research.  The first is that it is occurring with the acquiescence of government regulators. In particular,

It is worth mentioning that the [US] FDA [Food and Drug Administration] has encouraged this state of affairs, by viewing negative studies as uninformative, due to the possibility of being 'failed' rather than truly negative (ie, the sample may have simply been unresponsive, or dosing might have been too low and so on). Thus drugs could have two positive studies, and 10 or so negative ones (as did a number of selective serotonin reuptake inhibitors),8 and the FDA not only allowed approval but it did not require that the pharmaceutical industry publish its negative results. The pharmaceutical industry did the minimum necessary; the FDA set the minimum far below what should have been the acceptable scientific standard.

Furthermore, even though the FDA is supposed to allow access to information about all studies for drugs for which it provides an indication, in fact it still does not allow access to raw data from industry sponsored studies, which are viewed as confidential and proprietary. Rather, in my experience and those of colleagues who have attempted to access such studies, Freedom of Information Act requests are met with abstracted summary results. While summary results are better than no results, full access to scientific data should be the standard at the FDA.

The second is that medical journal reviewers and editors do not seem enthused about publishing articles about how research has been suppressed (an apparent example of the anechoic effect, or perhaps the anechoic effect squared, i.e., discussion of our failure to discuss research studies whose results did not please their sponsors is simply not done.)

In the course of trying to investigate and publicise these negative findings, we ran into numerous roadblocks, as I discussed in an interview for the Carlat Report last year

Instead of repeating what I have said before about the evils of suppressing clinical research, I will offer some concluding quotes from Dr Ghaemi.

Evidence based medicine—or, more simply put, the science of medicine—cannot be taken seriously, and is certainly not valid, if the evidence base is only partial. The scientific literature currently is like an under cooked meal which we think is ready to eat. We never know whether what we see in the evidence is correct or biased in one direction or the other. Meta-analyses of large published datasets are not as meaningful as they seem when unpublished data languish elsewhere.

Manipulation and suppression of clinical research has likely misled doctors and patients into using and paying too much for minimally effective, ineffective, or even harmful drugs and devices.  Manipulation and suppression of research is thus probably a major reason that health care costs much more than its value and accessibility warrants.  To truly reform health care, we should not let those with vested interests in selling health care products or services control the clinical research that purports to evaluate what they are selling.

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.