For today’s case study in maintaining the integrity of taxpayer-funded biomedical research, we launch ourselves 3,000 miles across the United States, to the leafy green campus of Stanford University, in sunny Palo Alto, California.
Isn’t the weather lovely?
Stanford maintains a web page devoted to its conflicts of interest policy and inquiries involving former department chairman Dr. Alan Schatzberg, who came under fire for his federally funded research of the drug mifepristone. The web page has links to almost 20 different documents, including public statements, a letter to The New York Review of Books, and several letters to Senator Charles Grassley (R-IA) and the National Institutes of Health (NIH).
What’s missing, you might ask?
Well, how about any press statement or other documents announcing that an NIH oversight group recommended that Stanford’s clinical trial on mifepristone be “terminated immediately and permanently.” The recommendation was made because of concerns over conflicts of interest, patient safety and other issues.
Why wouldn’t Stanford make this information publicly available online along with the numerous other documents? The information certainly seems to be of interest to the public.
Emails recently unearthed by POGO reveal this untold twist in the story of the mifepristone clinical trial. But before we dive in, let’s wind back the clock to 2008, when Senator Grassley began investigating Dr. Schatzberg for alleged cozy ties to the pharmaceutical industry.
Full disclosure: I am a former Grassley staffer and was the lead investigator on the senator’s work on Dr. Schatzberg and mifepristone.
A CLOSER LOOK
In 2008, Senator Grassley zeroed in on possible conflicts of interest involving Dr. Schatzberg’s grant from the National Institute of Mental Health (NIMH, which is a part of NIH) to study mifepristone as a possible treatment for depression. While overseeing this research, Dr. Schatzberg owned millions of shares in Corcept Therapeutics, a company that was attempting to get mifepristone approved by the FDA to treat depression.
“Dr. Schatzberg carries an equity interest in Corcept with over 2 million shares of stock,” Grassley explained in a letter to Stanford President John Hennessey. “For instance, as of January 31, 2008, he reported to the SEC that he held 2,438,749 shares of Corcept stock, with sole voting power for 2,738,749 shares. On June 12, 2008, Corcept stock closed at $2.24 a share, meaning that his stock is potentially worth over $6 million.”
Six million dollars, the Senator might have wondered. Is this a conflict?
Stanford put out an official statement, noting, among other things, that “Stanford and Dr. Schatzberg disclosed this conflict and the fact that Stanford was monitoring this conflict to the NIH. In addition, NIH reviews its data through the Data Safety Monitoring Board structures.”
Data Safety Monitoring Boards (DSMBs) monitor clinical trials to ensure participant safety and to protect the validity and integrity of data. The fact that Stanford is trumpeting the DSMB system seems good, no?
A few months later, in August 2008, Dr. Schatzberg stepped down as principal investigator of the NIH grant, and The Stanford Daily reported that Dr. Fredric Kraemer, a professor in the School of Medicine, was set to replace Dr. Schatzburg as the principal investigator on the grant. Stanford put out another statement:
Despite our belief that Stanford, NIMH, and Dr. Schatzberg have handled this grant in accordance with the regulations and applicable policies with due regard for the integrity of the research, we can see how having Dr. Schatzberg continue as the principal investigator on the grant can create an appearance of conflict of interest, and we want to eliminate that concern.
An appearance? No kidding.
Dr. Schatzberg himself sent a letter in September 2008 to the members of the American Psychiatric Association, an organization that had recently elected him as president, to address the “misperceptions and false statements” about his research and ethics. In that letter, Dr. Schatzberg characterized Grassley’s investigation of his taxpayer funded research and millions of shares in Corcept Therapeutics as an “attack.”
“Being attacked for doing good by those on the outside is something we must all combat with facts as I have in this letter and as Stanford has through its responses to the Senator,” wrote Dr. Schatzberg. He continued, “but we must also recognize and confront that we have our own internal destructive elements both in our profession and in our organization.”
Dr. Schatzberg also stressed the importance of the NIMH DSMB. “Part of our extensive discussion to address the conflict of interest question resulted in an NIMH DSMB that provides oversight for the grant.”
Hmmm….this DSMB thingy keeps coming up. Seems pretty important, no?
Stanford also sent several letters to the NIH to explain how they were handling the grant. A letter from late 2008 reads, “We look forward to moving quickly to get the NIMH Grant restructured so that Dr. Schatzberg’s research can continue.”
Stanford Vice President and General Counsel, Debra L. Zumwalt, continued with the “restructuring” concept in a letter sent to The New York Review of Books (NYR). In her letter, Ms. Zumwalt complained about an article on conflicts of interest written by Dr. Marcia Angell of Harvard University, in which Dr. Angell touched upon the issue of Dr. Schatzberg.
“The integrity and safety of the research were assured by the Data Safety Management [sic] Boards at both Stanford and the NIMH,” Ms. Zumwalt wrote.
Ms. Zumwalt added that “Stanford University, with the concurrence of Dr. Schatzberg, would temporarily appoint another faculty member as principal investigator while working with the NIMH to restructure the grant, to eliminate any misunderstanding of Dr. Schatzberg’s role in mifepristone research for those not familiar with the grant and federal oversight process.”
WHAT STANFORD HASN’T PUBLICLY DISCLOSED
On May 15, 2009, a few months after Ms. Zumwalt’s lecture appeared in the NYR, the much-ballyhooed NIMH DSMB met and discussed Stanford’s effort to “restructure” the grant. According to internal NIH emails, their unanimous recommendation was that the mifepristone clinical trial “should be terminated immediately and permanently.”
“This was done for multiple reasons,” one official wrote, “including inadequate recruitment to answer study questions, changes in Stanford’s COI [conflict of interest] Policy which would have halted the trial July 1, 2009 anyway, and concerns about ability of staff now working on this study to manage such difficult (psychologically depressed) participants.”
The next day, this same official wrote the head of the NIMH, “If they can utilize psychiatry staff, then maybe the baseline HPA [Hypothalamic–pituitary–adrenal] assessment component will still be viable, but we’re done with the mifepristone aspect.” The HPA assessment part of the grant was allowed to proceed after the NIH Board was satisfied that “the original potential COI has been managed by Stanford University,” according to a June 4 NIH e-mail.
The official also wrote: “The Stanford PIs [principal investigators] were notified within minutes of the DSMB Meeting.”
Both the mifepristone study and Stanford’s conflict of interest (COI) policy apparently came up in an email discussion later that month. Referring to another grant, a different NIH official wrote: “While this situation is not explicitly addressed in the 1995 Regs, it closely resembles the [REDACTED] situation strongly criticized by Senator Grassley in which an individual with a financial interest in the study outcome had supervisory authority over the clinical trial investigators.”
The official added, “FYI, Stanford has recently banned such arrangements in its new COI policy, and ordered the mifepristone study halted as of July 1; our NIMH DSMB ended the trial last week.”
Oddly enough, it appears that Stanford did not issue a press release announcing that the NIH informed either Stanford or Stanford researchers that the mifepristone clinical “should be terminated immediately and permanently.”
Furthermore, we were unable to locate any public statement on Stanford’s website announcing that Stanford’s updated conflict of interest policy bans, as the NIH official suggests, the type of research arrangement that attracted the scrutiny of Senator Grassley.
Even more concerning, POGO can’t find any record, press release, or public statement on the Stanford web page confirming or otherwise shedding light on the following statement by an NIH official, also found in the emails obtained by POGO:
The Stanford IRB [Institutional Review Board] is being informed, and OHRP will also need to be notified of this action. (Emphasis added)
The Department of Health and Human Services OHRP—the Office for Human Research Protections—is the HHS office that protects patients in federally funded trials. The apparent need to contact OHRP as well as the NIMH DSMB’s statement that there were patient safety concerns serious enough to warrant the trial’s termination is troubling.
Why wouldn’t Stanford publicly disclose this? If there were potential concerns about patient safety in the clinical trial, POGO thinks Stanford should have made this public, if Stanford is truly interested in transparency surrounding its publicly funded research.
In an email to POGO, Ms. Zumwalt denied that Stanford did anything wrong in not publicly disclosing the information contained in the NIMH DSMB emails. “No Congressional body asked any questions of Stanford with regard to this study in May 2009 or thereafter,” she wrote. She added, “Of course, NIH was fully aware of the facts and the emails.”
“I fail to see what you allege is Stanford’s failure to disclose this action on the study,” Ms. Zumwalt wrote.
-- Paul Thacker
Image of Stanford campus by Flickr user pshab, used under Creative Commons License.