The Zyprexa Chronicles: Bipolar Disorder Studies And Glucose Increases, "This May Be A True Assumption"

On October 11, 2002, Giedra Campbell emailed a group of Eli Lilly officials to "hammer out" clinical summary issues around at least one study on the use of Zyprexa in maintenance of bipolar disorder, according to a copy of the document I have reviewed. Campbell is a medical writer with the company. Among others, she emailed John Saunders, a Lilly regulatory affairs official in England, Doug Williamson, a doctor who was part of the Zyprexa Bipolar Team, and Mauricio Tohen. Tohen is a professor of psychiatry at the Harvard University School of Medicine and, at the same time, a Lilly employee. In other posts, I have noted that he is the primary author of many of the papers in the clinical literature on Zyprexa and that he designs the studies, which are then performed by outside researchers. Tohen is also a major shareholder of Lilly stock.

Campbell's purpose was to work out how Lilly should phrase language used in reporting what appear to be two separate studies--one gauging Zyprexa's performance as a monotherapy in the maintenance of bipolar disorder, another detailing Zyprexa's efficacy in combination with a mood stabilzer such as Lithium. Some of the language involved how to phrase data on glucose increases in patients in a company-sponsored study.

"John [Saunders] is ok with this explanation BUT has reservations about including it, because it operates on the assumption that olz [shorthand for olanzapine, Zyprexa's generic name] automatically increases glucose," Campbell writes in the email. "This may be a true assumption, but do we want to present this this way? Does inclusion of this explanation open us up to questions on glucose that we'd rather not bring up?"

It is not clear what was the earlier language to which Campbell refers. Lilly officials did not return a request for comment.

The principle data she refers to in the the email involved 361 patients with bipolar disorder who were given Zyprexa for 12 months, or a maintenance period, according to the document. At the time, Zyprexa was only approved for treating acute mania in bipolar disorder, in addition to its approved uses in schizophrenia. The company had plans to have the drug approved for maintenance, or long-term use, in bipolar disorder, as well as having it approved for use in combination with either Lithium or Depakote in bipolar disorder, according to other company documents I have reviewed.

The 361 patient study was an important one for Lilly. It appears in Zyprexa's current package insert as demonstrating the clinical efficacy of the drug in the long-term treatment of bipolar disorder. It is common for pharmaceutical companies to highlight studies for which their product gained regulatory approval in the package insert. A spokeswoman for the FDA did not return repeated requests to clarify whether this was the study used to later approve Zyprexa for maintenance use, as occurred in January 2004. Lilly officials did not return a request to clarify this point.

Campbell, the Lilly medical writer, notes in her email that of the 361 patients (225 taking Zyprexa, 136 taking a placebo), only 66 completed the entire one year trial without a recurrence of a manic, mixed or depressive episode or did not discontinue for another reason. She tells Saunders that she'd rewritten the study's language to "try to soften the 'only 66 completers' language." Almost 24 percent of Zyprexa patients in the study completed versus 9.6 percent of placebo patients. It is not clear how many of the 53 Zyprexa patients who completed the study experienced no symptom recurrence. I am unable to find the 361-patient study in the clinical literature. Lilly officials did not return a request to provide a published citation for the study.

In addition, Campbell's email details that in a study--apparently separate from the 361-patient study--of patients taking Zyprexa plus a mood stabilizer, the patients who took Zyprexa had a mean increase in glucose while patients who received a mood stabilizer and a placebo had a mean decrease in glucose. The mood stabilizer plus Zyprexa study was important, too. In 2003, not long after Campbell's email, the FDA approved Zyprexa for use in combination with Lithium or valproate (Depakote) for the treatment of acute manic episodes associated with bipolar disorder.

Regarding the glucose data language, Campbell pointed out to Tohen, Williamson and Richard Risser that "John [Saunders] suggests that if we include it, we need to pass it by Patrizia to check it against the company line on this topic." "Patrizia" is a reference to Patrizia Cavazzoni, a leading researcher at Lilly and co-author with Mauricio Tohen of several Zyprexa studies. "Mauricio--how strongly do you feel about including an explanation here?"

"I would like to include the FU glycemia issue because it points to the reversibility of the event," Tohen responded in a subsequent email on October 16, according to a copy of the document I have reviewed. "FU" refers to a code for one of the studies.

"But surely we want patients to stay on OLZ long-term, so the reversibility of the event is not an advantage?" Williamson, the doctor on the Zyprexa Bipolar Team, wrote to Tohen and others later on October 16.

It is not clear where the study's intended destination was, although in the email she refers to a department called "Publishing" and that she had mere days to get the final document to the department. Lilly officials did not return a request for comment.

In January 2004, Zyprexa was approved for long-term maintenance of bipolar disorder. In a press release, the company stated that "Zyprexa is the first treatment in nearly 30 years to be recognized by the FDA as a treatment for both acute mania and maintenance treatment in bipolar disorder." The treatment that had been approved 30 years before was Lithium, the so-called gold standard in treating bipolar disorder.

Quoted in the company press release is Frederick Goodwin, a psychiatrist at George Washington University Medical School and the godfather of psychopharmacology. "It is good news that the FDA has
now approved Zyprexa as a new tool for physicians to use to delay relapse and prolong periods of stability and wellness." It is not clear if Goodwin was aware of the glucose data.

NOTE: Reporting is based upon Zyprexa document number ZY200540696, which is available on this site's Zyprexa documents page.