The Zyprexa Chronicles: Marketing Zyprexa As The New Mood Stabilizer For Bipolar Disorder And Downplaying Diabetes And Weight Gain Concerns

This is an extremely lengthy post, one that requires use of the extended entry below, as well as numerous links to various Eli Lilly internal documents. Eli Lilly and the FDA were contacted repeatedly to answer questions. Neither replied.

Since mid-December, when the New York Times broke the news around accusations of alleged off-label marketing and alleged downplaying of risks associated with diabetes, weight gain and cardiac issues potentially connected with the use of Eli Lilly's Zyprexa, most of the resulting press attention, on and off-line, has focused on the drug's use in schizophrenia and dementia. In the latter condition, there have been accusations that Lilly marketed to drug off-label. The company has denied the accusations.

Little attention, however, has been focused on how Lilly targeted Zyprexa for use in bipolar disorder and how the company sought to change the medical treatment paradigm of patients with bipolar disorder by aggressively pushing doctors to use the drug, an antipsychotic, in mild cases of bipolar disorder, as opposed to cases of full-blown mania, and to use it as a long-term mood stabilizer along the lines of Lithium. This is not a minor matter. By some estimates, 50 percent of Zyprexa's $4.3 billion in sales comes from people taking the drug for bipolar disorder. The drug's use among these patients also potentially affects more patients, as bipolar disorder is estimated to affect from about six million to twelve million Americans. Schizophrenia is estimated to affect between two million to three million Americans.

As the company sought to turn Zyprexa into the "number one neuroscience drug in history," its strategy rested squarely in how much of the market for treating bipolar disorder it could carve off for Zyprexa. To do that, they cast Zyprexa as a long-term "mood stabilzer" far in advance of an FDA approval that would permit such language. Along the way, the company downplayed known risks associated with the drug.

CHASING BIPOLAR FROM THE START, WEIGHT GAIN CONCERNS

According to internal Lilly documents I have reviewed (and which I will link to throughout this post), the company aimed to go after this market more than a year in advance of Zyprexa's initial approval for schizophrenia in October 1996. In a document (3.9 MB) entitled (sic) "Zyprex--A Major Step Toward A Health Care solution For Psychosis" and dated July 20, 1995, "mania" is detailed as a new indication for the drug that the company planned to pursue in 1996 with "many" principle investigators at work on clinical research on the drug's use in mania (see page 43 of the lengthy document).

At the time, patients with bipolar disorder were commonly treated with a mood stabilizer such as Lithium, which had been approved for short and long-term maintenance use in the disorder since the 1970s. In some cases, an anti-depressant such as Lilly's Prozac would be added. Patients who experienced full-blown psychosis and were hospitalized were sometimes given an antipsychotic such as Mellaril, but only for short periods of time until the patient's condition stabilized. Some patients with mild symptoms of agitation, insomnia and racing thoughts might be given a small prescription of, say, Mellaril and be directed to take it for a few days only until their symptoms were properly knocked down. Mellaril is a "typical" or first-generation antipsychotic. Doctors were concerned that longer-term use of first-generation antipsychotics would lead to tardive dyskinesia and extrapyramidal symptoms and that such risks were not worth running when psychosis in bipolar mania tends to be short-lived and transient as compared with psychosis in schizophrenia.

Zyprexa was dogged by concerns of weight gain as far back as 1996 and Lilly's response, as it would be in later years, was to downplay concerns of weight gain. On October 1, 1996, Zyprexa was approved by the FDA for use in schizophrenia. The week before, it had been approved in Europe. Gary Tollefson, a Lilly official on its ironically-named "Heavyweight Team," conducted a conference call that day with several reporters to announce "the good news of the Zyprexa story." One reporter asked about initial reports of weight gain in some patients. Tollefson downplayed the concern, saying it was reported with all antipsychotics and that the patients were sometimes so underweight that the weight gain could be seen "in the majority of patients as being part of therapeutic recovery rather than an adverse event."

GOING AFTER LITHIUM, CHANGING THE PARADIGM

In a document (3.5 MB) from 1997, in which the company sought to "tee-up critical issues for the next 3-year planning cycle," company officials note that Lithium, an inexpensive generic product, was still the market leader in treating bipolar disorder. The company goes on to identify bipolar disorder as its number one goal for "disease state prioritization."

"Zyprexa will be the world's number one neuroscience drug in history," the document, authored by Tollefson, states in outlining the company's "strategic intent" for the drug. The company projected sales of $700 million for the drug in 1997, its first full year in the marketplace.

The company forecast that in the second half of 1998, Zyprexa would generate "'Depakote-like' uptake as a mood stabilizer," and already had a vision for its long-term use in treating bipolar disorder.

Both Lithium and Depakote were commonly referred to as mood stabilzers and were used in patients long-term. In Lithium's case, patients could well be on the medication for a lifetime (Depakote had only been used in bipolar disorder since the early-1990s.)

"To be a leader in the bipolar market, Zyprexa will need to be viewed as [a] true mood stabilizer (emphasis Lilly's). A true mood stabilizer will work in acute manic episodes without inducing depression, acute bipolar depression without inducing mania, and protect the patient from future episodes of mania or depression (emphasis mine)."

To "change the bipolar treatment paradigm" was seen as a major opportunity by the company, one that had "huge potential for (sic) increase in sales/value to Zyprexa and Lilly," according to the 1997 document. Weight gain was identified as one weakness of the drug, as was its cost relative to Lithium and Depakote. Zyprexa, at the time, cost on the order of ten times as much as a comparable dosage of Lithium.

As part of its bipolar marketing plans for Zyprexa, the company "planned/needed" bipolar disorder screening at the 1998 National Depression Screening Day, an activity sometimes carried out by the National Alliance for Mental Illness, as well as public relations programs aimed at journalists and grassroots media. In addition, the company hoped for an "Erasing the Stigma" partnership with the Rotary Club. The company planned to submit the drug for an acute mania indication with the FDA in 1998, according to the document. In 1999, the company hoped to have a celebrity spokesman on board.

"Zyprexa is a profound corporate opportunity," the document states. The company forecast as much as $1.1 billion in sales to bipolar disorder patients by the end of 2000.

"HIGH BLOOD SUGARS"

But in 1999, unsettling reports began to come in from clinicians. In a November 12, 1999letter (second part of letter here) from Albert Marrero, a staff psychiatrist with the Ventura County Behavioral Health Department, to Lilly's medical director, "high blood sugars" were cited as a problem.

"We have had eight patients out of possibly thirty-five patients on Zyprexa show up with high blood sugars," Marrero's letter states. "Two patients had to be hospitalized due to out of control diabetes....We have certainly never seen this with Haldol, Navane, Risperdal and others to this extent." It is not clear whether the patients were being treated for schizophrenia or bipolar disorder.

The drug was approved for short-term use in acute bipolar mania on March 17, 2000. Eli Lilly was prepared to change the paradigm.

THE ZYPREXA BIPOLAR LAUNCH

In March 2000, Lilly began a massive roll out of the drug for bipolar disorder. In a document from that month, the company detailed numerous marketing activities aimed at psychiatrists, according to the company document. A satellite symposium had been scheduled for February 23. Entitled "Clinical Management of the Bipolar Spectrum for the New Millennium," the program featured thought leaders in psychiatry such as Paul Keck, a psychiatrist at the University of Cincinnati School of Medicine, and was targeted at 6,000 doctors at 1,000 facilities and would also include 8,000 treatment team members such as nurses and social workers.

In addition, plans called for 15 bipolar dinner meetings, staged as continuing medical education events, and entitled "Restoring Balance: Long-Term Mood Stabilization in the Bipolar Patient." (Emphasis mine.) Anywhere from 150 to 400 psychiatrists were expected for each dinner. Lilly sales reps would attend as well, according to the document.

At the time, Zyprexa was not approved for long-term use.

It is not clear if such an event amounted to off-label marketing of Zyprexa for long-term maintenance use in bipolar disorder. Off-label marketing rules are murky and the FDA has not responded to repeated requests to clarify the matter. Neither has Eli Lilly. In general, companies can only market drugs to physicians for approved use. But doctors, paid by a company to speak for their product, have much more leeway to make broad statements about a drug's use, on or off-label, than do company sales reps, for example.

The company also planned to distribute a one-page "sell sheet" to 30,000 psychiatrists (that would be almost every psychiatrist in the US) and 95,000 pharmacists. In addition, Lilly planned to hold 30 regional "psychosis/bipolar weekend symposia" between April and November of 2000. Lilly also planned several other direct-to-physician initiatives between January and June 2000. The campaign aimed to "capitalize on reintegration, evolve private psych message to include depression data, neutralize weight gain." It consisted of a program called "dawn of a new era in treating schizophrenia and bipolar disorder."

The company had no indication for Zyprexa's use in depression.

In addition, Lilly planned to blast fax 30,000 psychiatrists every other month for three years with "schizophrenia, bipolar, elderly and health econ data," according to the document.

2001: BIPOLAR MAINTENANCE, LILLY DOWNPLAYS DOCTORS CONCERNS

In an "Integrated Product Plan" from January 18, 2001, it is clear that the company was pursuing indications for bipolar maintenance in the European Union and the US, according to a company document. In a separate document, the Zyprexa product team identifies "the Bipolar patient: mania, maintenance, depression" as one of its "2001 priorities."

Zyprexa was not approved for either depression or maintenance use in bipolar disorder at the time. It is not clear if the product team's priority for bipolar disorder translated into activities by Lilly's sales force in regard to long-term use of the drug. Lilly did not return repeated requests for comment.

But there was other troubling news afoot concerning perceptions about Zyprexa's side effects.

In April 2001 survey, 100 percent of psychiatrists surveyed believed that there was link between Zyprexa and diabetes and hyperglycemia. In this document, it is stated that the perception existed because some doctors were more selectively assessing their patients for diabetes and hyperglycemia if they are on Zyprexa, and, also, because more of their patients were on Zyprexa.

In a May 31, 2001 email, a company official reports on an FDA symposium called "Evaluating a Safety Signal in the Postmarketing Period: Hyperglycemia and the Atypical Antipsychotic Drugs." The symposium was led by Judith Racoosin, an FDA official. During a question and anser session, an audience member asked, "Where is the FDA headed with atypicals and diabetes?" according to the email.

"No decisions have been made" was Racoosin's reply.

A YEAR OF JAPANESE LABEL CHANGES

Lilly knew that a reckoning would soon be at hand for Zyprexa and concerns about hyperglycemia, weight gain and diabetes connected with its use. On January 30, 2002, the company's medical liaison in Texas emailed company officials to let them know of ongoing developments in that state's mental health system. Shelethea Dunning, the medical liaison, noted that Texas officials were hatching plans to have patients going onto Zyprexa go through baseline monitoring for glucose and weight, and to be continually monitored for changes. She explained that it was important for the company to do another presentation to researchers in charge of the state's so-called Texas Medical Algorithm Project, a highly-influential set of guidelines which was often used around the country as a tool for psychiatrists and other doctors in determining what medication to give to what patient. Dunning noted that TMAP researchers "are viewed as national leaders in mental health."

It is not clear what actions Lilly subsequently took. The company was soon faced with an even more serious challenge from abroad.

On April 15, 2002, Lilly learned that Japanese health officials would require a labeling change in that country. The label, according to a Lilly document, would instruct doctors not to use Zyprexa in patients with diabetes or in patients with a history of diabetes. The warning would also indicate that there was an increase in blood glucose for patients taking the drug. "Strongly disagrees" is what Lilly's assessment was of the Japanese decision.

"This does not change the status of Zyprexa as a safe, effective and cost effective agent in the US market," the internal document also states.

Lilly did not return a request for comment to clarify how the drug could be viewed as connected with diabetes in Japan but not in the US. The FDA did not return a request to clarify the same point and did not return a request to reveal what response the FDA undertook in light of the Japanese label change.

Within two months, Lilly showed just how much it disagreed with Japanese health officials.

"DONNA" AND LILLY'S MOVE INTO THE PCP MARKET

In June 2002, Lilly rolled out a new sales initiative for Zyprexa. The initiative was dubbed the "Zyprexa Limitless Team" and would create a primary care sales force targeting family practitioners, internists and other primary care physicians (PCPs) in an effort to sell them on using Zyprexa to treat patients in their practice who presented complaining of mixed mood symptoms such as agitation, insomnia and depression. The symptoms are considered hallmarks of bipolar disorder type 2 and cyclothymia, lighter forms of the disorder which stop far short of the psychoses and hospitalizations that are specific to bipolar disorder type 1 (or classic manic-depression).

The move into the PCP market was part of Lilly's long-held plan to reshape how bipolar disorder was treated. An estimated 50 percent of mental health care in America is delivered by PCPs, most commonly for depression. Typically, PCPs almost always refer patients with schizophrenia and bipolar disorder, key markets for Zyprexa, to psychiatrists much as PCPs refer patients with heart problems to cardiologists.

"Just as Prozac revolutionized the treatment of depression in the late 80s and throughout the 90s, so too will Zyprexa forever change the way primary care physicians view and treat bp disorder," the company states in a resource guide for sales reps. The company estimated bipolar disorder's prevalence in the American population at 6 percent. At the time, the National Institute of Mental Health estimated that the prevalence was a bit over 1 percent.

"We can change their paradigm," the document states. To do so, the company turned to "Donna," a hypothetical patient. It's customary in pharmaceutical sales to talk with doctors about hypothetical patient profiles and for the salesperson to work to convince the doctor that their product is what the doctor should be using on patients who meet that profile.

Donna, "a single mom in her mid-30s," was not even close to being a classic manic-depressive. She came into her doctor's office "seeming somewhat ill at ease. Her chief complaint is, 'I feel so anxious and irritable lately.' Today, she says she's been sleeping more than usual," continues the sales guide, "and has trouble concentrating at work and at home."

In a separate document from the campaign, sales reps are instructed to present Donna in such a way as to "make sure the kind of patient we are talking about today, [is] not the psychotic patient or severely ill patient, but the complicated mood patient."

The answer to Donna's problem was to be treated with Zyprexa, starting at a 5 mg. daily dose, roughly equivalent to 3 mgs. of Risperdal. "If her symptoms persist after one week, it is important to increase the dose to 10 mg--and you can feel comfortable doing so with Zyprexa's safety profile."

In the Donna script, the only safety issues addressed are those of other drugs and how Zyprexa compares favorably. The document states that older antipsychotics cause extrapyramidal symptoms--a truism--and that Zyprexa doesn't. In addition, the document states that Risperdal caused heightened prolactin levels in patients, but that Zyprexa did not.

"You will be able to assure Donna that Zyprexa is safe and that it will help to relieve the symptoms she is struggling with," the sales script states.

Nowhere in this Donna script is hyperglycemia or potential risks of diabetes mentioned, despite the fact that such risks were well-known at the time. As mentioned above, only six weeks earlier, the Japanese government had found such risks worthy of a serious label change for the drug.

"I would like you to get a patient like Donna started today," the script continues. "I will be back in a week to follow up."

In an undated "hyperglycemia/diabetes sell sheet implementation" document, the company notes, "Our goal and focus is on creating a market with Donna. The competition wins if we are distracted into talking about diabetes."

Nowhere does this Donna script instruct sales reps to communicate with PCPs about weight gain concerns. But the concerns were so prevalent among psychiatrists that a report from Lilly focus groups in March 2002 reported that psychiatrists saw a "100 percent association" between Zyprexa and weight gain.

In an undated document from the PCP campaign, sales reps are instructed in how to handle "frequent areas of concern" that might be brought up by some doctors. Reps were instructed to handle questions of weight gain by pointing out that "Zyprexa may cause an increase in appetite that can lead to weight gain....You can suggest that patients drink diet soda instead of regular soda or cut back on the amount of carbohydrates they eat."

Sales reps, in the same document, were instructed to handle diabetes concerns by stating that rates were comparable among all atypical antipsychotics. Not everyone believed the claim, however.

On Setpember 5, 2002, Lilly recived a letter from James Turnbull, an official at Frontier Health in Kingsport, Tenn. He explained to Lilly that 10 percent of their patients taking Zyprexa see changes in glucose, trigylcerides and cholesterol, as he had pointed out to the company in an earlier letter. Turnbull was not pleased with the company's reply, which I have not seen. "It just confirms the theory that there are lies, damn lies and statistics," he wrote.

As I reported last week, in October 2002 a Lilly medical writer exchanged emails with several company officials trying to "hammer out" how the company would characterize glucose production that arose in recent clinical studies of Zyprexa in the long-term treatment of bipolar disorder. The company was preparing submissions to the FDA to have the drug approved for maintenance use in bipolar disorder.

"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," [medical writer] 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?"

In 2001, Zyprexa sales were approximately $3.3 billion. For 2002, the company reported sales of $4 billion, a 21 percent increase over the previous year, according to IMS Health.

AVOID REFERRING TO ZYPREXA AS MOOD STABILIZER

Double-digit sales gains were met with consternation by Lilly. In a 2003 "Brand Council" document (5 MB), the company describes its frustrations. The document is marked "for strategy and evaluation purposes." It called for hitting $6 billion in sales by 2006.

"Zyprexa obtains 'foundation of treatment' in bipolar in the US," the document states, but "only vs. AP's," meaning only in comparison with other atypical antipsychotics but not against mood stabilizers such as Lithium and Depakote. The company felt "significant" sales gains were possible in a "short time."

Still, the document states that Lilly should "avoid referring to Zyprexa as a mood stabilizer." The company expected a new indication for bipolar maintenance in early 2004.

On January 14, 2004, the FDA approved Zyprexa for use in bipolar maintenance. The company's press release cast the approval thus:

"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 other treatment approved for maintenance use was Lithium.

Posted by Philip Dawdy at February 21, 2007 02:28 AM
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