Drug Files Show Maker Promoted Unapproved Use
Source: NY Times
Eli Lilly encouraged primary care physicians to use Zyprexa, a powerful drug for schizophrenia and biploar disorder, in patients who did not have either condition, according to internal Lilly marketing materials.
The marketing documents, given to The New York Times by a lawyerrepresenting mentally ill patients, detail a multiyear promotionalcampaign that Lilly began in Orlando, Fla., in late 2000. In thecampaign, called Viva Zyprexa, Lilly told its sales representatives tosuggest that doctors prescribe Zyprexa to older patients with symptomsof dementia.
A Lilly executive said that she could not comment on specificdocuments but that the company had never promoted Zyprexa for off-labeluses and that it always showed the marketing materials used by itssales representatives to the Food and Drug Administration, as required by law.
“We have extensive training for sales reps to assure that theyprovide information to the doctors that’s within the scope of theprescribing information approved by the F.D.A.,” Anne Nobles, Lilly’svice president for corporate affairs, said in an interview yesterday.
Zyprexa is not approved to treat dementia or dementia-relatedpsychosis, and in fact carries a prominent warning from the F.D.A. thatit increases the risk of death in older patients with dementia-relatedpsychosis. Federal laws bar drug makers from promoting prescriptiondrugs for conditions for which they have not been approved — a practiceknown as off-label prescription — although doctors can prescribe drugsto any patient they wish.
Yet in 1999 and 2000 Lilly considered ways to convince primary caredoctors that they should use Zyprexa on their patients. In onedocument, an unnamed Lilly marketing executive wrote that these doctors“do treat dementia” but “do not treat bipolar; schizophrenia is handledby psychiatrists.”
As a result, “dementia should be first message,” of a campaign toprimary doctors, according to the document, which appears to be part ofa larger marketing presentation but is not marked more specifically.
Later, the same document says that some primary care doctors “might prescribe outside of label.”
Ms. Nobles said that the company had never promoted its drug for anyconditions except schizophrenia and bipolar disorder. Older patientswho seem to have dementia may actually have schizophrenia that has goneuntreated, Ms. Nobles said.
Several psychiatrists outside the company said yesterday that theystrongly disagreed with Lilly’s claim. Schizophrenia is a severedisease that is almost always diagnosed when patients are in theirteens or 20s. Its symptoms could not be confused with mild dementia,these doctors said.
Zyprexa is by far Lilly’s best-selling product, with $4.2 billion insales in 2005, 30 percent of its overall revenues. About two millionpeople worldwide received it last year. Based in Indianapolis, Lilly isthe sixth-largest American drug company.
The issue of off-label marketing is controversial in the drugindustry. Nearly every company is under either civil or criminalinvestigation for alleged efforts to expand the use of its drugs beyondthe specific illness or condition for which they are approved.
Lilly faces federal and state investigations over its marketing ofZyprexa. In its annual report for 2005, Lilly said that it faced aninvestigation by federal prosecutors in Pennsylvania and that theFlorida attorney general’s office had subpoenaed the company “seekingproduction of documents relating to sales of Zyprexa and our marketingand promotional practices with respect to Zyprexa.”
Since Lilly introduced Zyprexa in 1996, about 20 million patientsworldwide have received the drug, which helps control thehallucinations and delusions associated with schizophrenia and severemania. But Zyprexa also causes weight gain in many patients, and theAmerican Diabetes Association found in 2004 that Zyprexa was more likely to cause diabetes than other widely used drugs for schizophrenia.
Lilly says that no link between Zyprexa and diabetes has been proven.
As part of the “Viva Zyprexa” campaign, in packets for its salesrepresentatives, Eli Lilly created the profiles of patients whom itsaid would be suitable candidates for Zyprexa. Representatives weretold to discuss the patient profiles with doctors. One of the patientswas a woman in her 20s who showed mild symptoms of schizophrenia, whileanother was a man in his 40s who appeared to have bipolar disorder.
The third patient was “Martha,” a widow with adult children “wholives independently and has been your patient for some time.” Marthawas described as being agitated and having disturbed sleep, but withoutthe symptoms of paranoia or mania that typically marked a person withschizophrenia or bipolar disorder.
Ms. Nobles said that Lilly had actually intended Martha’s profile torepresent a patient with schizophrenia. But psychiatrists outside thecompany said this claim defied credibility, especially given Martha’sage. Instead, she appeared to have mild dementia, they said.
“It’d be very unusual for this to be a schizophrenic patient,” said Dr. John March, chief of child and adolescent psychiatry atmedical center. “Schizophrenia is a disease of teenagers and youngadults.” Dr. March serves on Lilly’s scientific advisory board.
Diagnostic criteria for schizophrenia include delusions,hallucinations, disorganized and incoherent speech, and grosslydisorganized behavior. They also include so-called negative symptomslike social isolation and a flattening of the voice and facialexpressions.
The documents also show that Lilly encouraged primary care doctorsto treat the symptoms and behaviors of schizophrenia and bipolardisorder even if the doctors had not actually diagnosed those diseasesin their patients. Lilly’s market research had found that many primarycare doctors did not consider themselves qualified to treat people withschizophrenia or severe bipolar disorder.
The campaign was successful, the documents show. By March 2001,about three months after the start of Viva Zyprexa, the campaign hadled to 49,000 new prescriptions, according to a presentation thatMichael Bandick, the brand manager for Zyprexa, gave at a nationalmeeting of Lilly sales representatives in Dallas. Mr. Bandick did notsay how many of those new prescriptions were for older patients withdementia.
Over all, sales of Zyprexa doubled between 1999 and 2002, risingfrom $1.5 billion to $3 billion in the United States. In 2002, thecompany changed the name of the primary care campaign to “ZyprexaLimitless” and began to focus on people with mild bipolar disorder whohad previously been diagnosed as depressed — even though Zyprexa hasbeen approved only for the treatment of mania in bipolar disorder, not depression.
In a 2002 guide for representatives, Lilly presented the profile of“Donna,” a single mother in her mid-30s whose “chief complaint is, ‘Ifeel so anxious and irritable lately.’ ” Several doctors’ appointmentsearlier, she was “talkative, elated, and reported little need forsleep.”
Lilly’s efforts to promote Zyprexa to primary care doctors disturbedsome physicians, the documents show. In August 2001, a doctor inVirginia sent an e-mail message to Lilly and the F.D.A., complainingabout a presentation from a Lilly sales representative who haddiscussed the hypothetical Martha with him.
The representative “presented an elderly female patient who was presented to her physician by her family complaining of insomnia, agitation, slight confusion, and had no physical finding to explain herstate,” the doctor wrote. The representative then suggested that thedoctor prescribe Zyprexa.
“I inquired what Zyprexa was indicated for she then indicated thatmany physicians might prescribe an antipsychotic for this patient. Ithen asked for her package insert and read to her that her product wasindicated for schizophrenia and bipolar mania — neither of which thepresented patient had been diagnosed with,” the doctor wrote.
He added that he had never contacted the F.D.A. before but was“genuinely concerned about the promotion of this powerful drug to mypeer community of primary care physicians outside of its approved andintended purpose.”
Tara Ryker, a spokeswoman for Lilly, said the company no longer uses“Martha” or “Donna” in its marketing. “We are constantly developing newpromotional materials and new profiles,” she said.
The Zyprexa documents were provided to The Times by James B.Gottstein, a lawyer who represents mentally ill patients and has suedthe state of Alaska over its efforts to force patients to takepsychiatric medicines against their will.
Mr. Gottstein said yesterday that the information in the documentsshould be available to patients and doctors, as well as judges whooversee the hearings that are required before people can be forced totake psychiatric drugs.
“The courts should have this information before they order thisstuff injected into people’s unwilling bodies,” Mr. Gottstein said.
Lilly originally provided the documents, under seal, to plaintiffslawyers who sued the company claiming their clients developed diabetesfrom taking Zyprexa. Last year, Lilly agreed to pay $700 million tosettle about 8,000 of the claims, but thousands more are pending. Mr.Gottstein, who is not subject to the confidentiality agreement thatcovers the product liability suits, subpoenaed the documents in earlyDecember from a person involved in the suits.
The “Viva Zyprexa” documents also provide color about Lilly’sefforts to motivate its sales force as they marketed Zyprexa — whosegeneric name is olanzapine — to primary care doctors.
At the 2001 meeting in Dallas with Zyprexa sales representatives,Mr. Bandick praised 16 representatives by name for the number ofprescriptions they had convinced doctors to write, according to ascript prepared in advance of the meeting. More than 100 otherrepresentatives had convinced doctors to write at least 16 extraprescriptions and thus “maxed out on a pretty sweet incentive,” he said.
“Olanzapine is the molecule that keeps on giving,” Mr. Bandick said.