Lilly Off-Label Promotion

Eli Lilly and Company pleaded guilty on January 30 to one misdemeanor violation of misbranding Zyprexa (olanzapine) by promoting it for dementia. However, a question raised by bloggers and others remains: did the drug benefit the elderly despite the fact it was not approved by the FDA for such purposes?

“Off-label promotion is an important legal issue,” said geriatric psychiatrist David Sultzer, MD, professor of psychiatry and biobehavioral sciences at the University of California, Los Angeles. “But off-label prescribing isn’t equivalent to unethical or inappropriate use.”

“Off-label prescribing of drugs is widespread, dependent on several factors, and not necessarily a bad thing,” he noted. “However, clinicians need to be making wise decisions with off-label use because the drugs aren’t approved for that use and the evidence base may be limited.”

Off-label marketing

In mid-January, the Department of Justice filed a criminal information against Lilly. (A criminal information is an accusation. A defendant is presumed innocent unless and until proved guilty.) It alleged that the company, among other actions, engaged in off-label marketing by promoting Zyprexa for elderly patients with dementia and with sleep disorders; that Lilly knew significant weight gain was an adverse effect of the drug but touted it as a therapeutic benefit; that Lilly instructed its sales force to recommend Zyprexa for adult patients with behavioral symptoms, such as agitation, aggression, hostility, and mood and sleep disturbances; and that Lilly’s management created marketing materials that promoted off-label uses.

Angela Sekston, executive director of external communications and corporate social responsibility for Lilly, told Psychiatric Times that the “company deeply regrets” its conduct related to promoting the drug for Alzheimer disease/dementia between September 1999 and March 31, 2001, but it does not agree with some of the broader claims and “acknowledges no wrongdoing here in the court records.”

After Lilly pleaded guilty to the misdemeanor count, District Court Judge Robert Kelly imposed sentence, and ordered the Indiana-based company to pay $515 million-one of the largest individual corporate criminal fines in history-and to forfeit an additional $100 million in assets.

Lilly also signed a civil settlement to resolve claims that by marketing Zyprexa for unapproved uses, it caused false claims for payment to be submitted to federal insurance programs, such as Medicaid, TRICARE, and the Federal Employee Health Benefits Program. None of these programs provided coverage for such off-label uses, according to a Department of Justice statement.

Under the settlement, Lilly pays an additional $800 million to the federal government and the states to resolve civil allegations originally brought in 4 separate lawsuits under the qui tam provision of the federal False Claims Act. The federal share of the settlement amount is $438,171,543, of which $78,870,877 will go to whistleblowers-former sales representatives who identified Lilly’s off-label marketing practices. The state Medicaid programs and the District of Columbia will share up to $361,828,456 of the civil settlement, depending on the number of states that participate. For example, California is expected to recover $54 million for its Medi-Cal program. Florida is expected to get $35 million.

Regarding the civil settlement, Lilly said in a January 15 press statement, “Even though the company disagrees with and does not admit to the civil allegations, the company has agreed to settle the dispute over these allegations.”

We have been cooperating with the government for 5 years on this investigation, Sekston said, adding that it has been a costly and significant distraction from the company’s core mission.

“With this settlement approved, we are pleased to be putting a significant amount of the Zyprexa litigation matters behind us,” she said.

Beyond the current criminal and civil settlement, last October Lilly agreed to pay $62 million to 33 states to settle claims that it improperly marketed Zyprexa to patients who did not have schizophrenia or bipolar disorder, the drug’s only approved uses. Last March, Lilly agreed to pay $15 million to Alaska to settle a lawsuit claiming that Zyprexa triggered the development of diabetes.

More civil cases are expected. According to press reports, insurers, pension funds, and unions have accused Lilly of suppressing information about the adverse effects of Zyprexa, such as weight gain and diabetes, and promoting the drug for other uses.

While the fines and settlement costs surrounding Zyprexa are substantial, a New York Times article (January 15) reported that since 1996, Zyprexa has generated more than $39 billion in sales. Roughly half of those sales were for off-label use. For 2008, Lilly reported worldwide Zyprexa sales of $4.696 billion-a 1% decrease from 2007. Sales in this country were $2.203 billion-a 1% decrease “driven by lower demand, partially offset by higher prices.”

Compliance and physicians

Of particular importance to clinicians and continuing education providers is a 5-year Corporate Integrity Agreement (CIA) that the company has entered into with the Health and Human Services’ Office of Inspector General as part of its settlement. It requires Lilly to cease off-label marketing and to establish programs to prevent the illegal conduct from recurring.

The CIA requires, among other things that Lilly send doctors a letter notifying them about the global settlement and how they can report questionable practices by Lilly’s representatives. It also requires Lilly to disclose its financial support of third-party educational activities and financial relationships with faculty, speakers, or organizers. The company must also post on its Web site, information about payments to US-based doctors or “related entities,” for honoraria, consultant services, and reimbursement for travel or lodging.

Sekston pointed out that Lilly is committed to its transparency initiative. Since 2004, it has had a clinical trial registry Web site (www.lillytrials.com) and since 2007, has posted online all educational grant funding and other monetary contributions provided to US-based organization, www.lillygrantoffice.com.

“We have also committed to launch the health care professional payment registry this year . . . in an effort to build further trust among the public,” she said.

Clinical use

Since its introduction, Zyprexa has been prescribed for an estimated 26 million patients worldwide, according to Lilly’s January 15 press statement. In the US, the drug is indicated for the short- and long-term treatment of schizophrenia, acute mixed or manic episodes of bipolar I disorder, and maintenance treatment of bipolar disorder. Zyprexa is not approved for patients younger than 18 years or for patients with dementia-related psychosis.

Yet, behavioral and psychiatric symptoms develop in as many as 60% of community-dwelling patients who have dementia and in more than 80% of patients with dementia living in nursing homes, according to a 2008 paper prepared by Jeste and colleagues.¹ The prevalence of specific symptoms in patients with Alzheimer disease varies: for delusions, the prevalence is 9% to 63%; for hallucinations, 4% to 41%; for physical aggression, 11% to 46%; and for agitation, 20% to 80%.

Randomized controlled trials of antipsychotics for psychosis and/or agitation associated with dementia, “in aggregate,” suggest modest efficacy in symptom reduction with active treatment compared with placebo, according to Jeste and colleagues. These researchers added, however, that several individual trials have yielded negative results.

The NIMH sponsored the CATIE-AD trial (Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer’s Disease) of atypical antipsychotics for psychosis or agitation/aggression in people with dementia. In this 42-site, double-blind, placebo-controlled trial, 421 outpatients with Alzheimer disease and psychosis, aggression, or agitation, were randomly assigned to receive flexible dose olanzapine (mean dose, 5.5 mg/d), quetiapine (Seroquel; mean dose, 56.5 mg/d), risperidone (Risperdal; mean dose, 1.0 mg/d), or placebo. Doses were adjusted as needed, and patients were monitored for up to 9 months.

The main outcomes were the time from initial treatment to the discontinuation of treatment for any reason and the number of patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale at 12 weeks. Researchers found that olanzapine, quetiapine, and risperidone were no better than placebo for the primary outcome (time to discontinuation for any reason).²

The time to discontinuation because of lack of efficacy was longer for active medicines (ie, beneficial), said Sultzer, one of the lead investigators in the CATIE-AD trial.

“So if the rationale for change was that they didn’t seem to be working well enough, antipsychotics won, but when the change was due to adverse effects, placebo won, so when you add them together, it was essentially a wash,” he said.

More recently, the CATIE-AD study group published a paper exploring possible antipsychotic treatment effects on distinct symptoms.³ Sultzer, director of the Gero/Neuropsychiatry Division of the VA Greater Los Angeles Healthcare System, was the first author.

“Our goal was to try to understand whether there was a particular kind of symptom that may respond better to antipsychotics compared to placebo,” Sultzer explained.

If you looked at a global symptom measure, there was a significant effect of risperidone and olanzapine treatment over placebo, based on rating scale scores at the time that initial phase ended, he said. Symptoms of hostility, aggression, anger, and paranoia responded best to antipsychotic treatment, although the improvement was modest on average, and many patients still had symptoms.

The differences between the 3 antipsychotics were fairly small, partly because the overall effects were mild. Sultzer added that from a research design standpoint, distinguishing between the medications was challenging.

Quetiapine did not do as well, but that may be related to a dosing issue, because the doses of quetiapine were relatively low, although there were some adverse effects, he said. But between olanzapine and risperidone, “there were few differences.”

In relation to placebo, the last observation in phase 1 of CATIE-AD showed greater improvement with olanzapine or risperidone on the Neuropsychiatric Inventory total score, and improvement with risperidone on the CGIC. Patients treated with risperidone or olanzapine showed improvement on the Brief Psychiatric Rating Scale (BPRS) hostile suspiciousness factor. The BPRS psychosis factor also improved with risperidone.

However, “antipsychotic treatment effects on the BPRS agitation factor score, which includes excitability, tension, and anxiety were not as robust,” according to Sultzer and his coauthors.

Nor were beneficial effects apparent on measures of functional abilities, quality of life, or time needed for care giving.

“The olanzapine group actually did a little worse than the other antipsychotics and placebo for outcomes such as patients’ functional abilities and rating of blunted affect and emotional withdrawal,” said Sultzer.

In CATIE-AD when the clinician felt that the original medication was less than ideal, he or she could move to phase 2 and prescribe one of the other 2 antipsychotics not used in phase 1, or citalopram (Celexa).

“The data for phase 2 of CATIE-AD have not yet been published,” Sultzer said. “At this stage it looks like the overall difference between antipsychotics and citalopram is not significant.”

In addition, Sultzer said, we are continuing to work with the CATIE data set, looking specifically at whether we can predict who is more likely to respond to treatment or who might be at greater risk.

The CATIE-AD researchers emphasized the need for additional studies to better understand the risk-benefit profile and effectiveness of specific treatments in individual patients. One such study is looking at the adverse effects of newer antipsychotics in older adults.

“Ours is an NIMH-funded 5-year study of the effects of 4 different atypical antipsychotics (aripiprazole [Abilify], olanzapine, quetiapine, and risperidone) in middle-aged and older people with psychotic disorders, for whom atypical antipsychotics are prescribed by the individual patients’ own treating physicians,” said Dilip Jeste, MD, distinguished professor of psychiatry and neurosciences at the University of California, San Diego, and director of the Sam and Rose Stein Institute for Research on Aging. “We use equipoise-stratified randomization, which allows the patients and their doctors to exclude up to 2 of the 4 medications from the list.”

The purpose of the study, Jeste said, is to compare the therapeutic and adverse effects of these atypical agents in patients 40 years and older. The researchers have completed two-thirds of the study but have not published any findings yet.

A recently published retrospective study funded by Department of Health and Human Services’ Agency for Healthcare Research and Quality looked at the effects of antipsychotics on the heart.⁴

Lead researcher Wayne A. Ray, PhD, of Vanderbilt University and his colleagues reviewed medical records from Tennessee’s Medicaid program, involving patients aged 30 to 74 years. The preliminary analysis included 44,218 users of typical antipsychotics, 46,089 users of atypical antipsychotics, and 186,000 matched nonusers. Current users of atypical antipsychotics, such as risperidone, quetiapine, olanzapine, or clozapine (Clozaril), had a rate of sudden cardiac death twice that of nonusers of antipsychotic drugs and similar to the death rate for patients taking typical antipsychotics. For both classes of antipsychotics, the risk for current users increased significantly with an increasing dose, but there was an absence of significantly increased risk among former users of antipsychotic drugs.

Commenting on this study, Schneeweiss and Avorn5 asked whether the use of antipsychotic medications should be restricted on the basis of these data. “Much of their use is in vulnerable populations and outside the labeled indications, including the use in children and in the elderly with dementia, and there is much less evidence of efficacy in these populations,” they said. “For these patients, the use of antipsychotic medications should be reduced sharply, perhaps by requiring an age-dependent justification for their use.”

Sultzer, whose clinical practice is in Alzheimer disease, said that because of the issues of mortality, cerebrovascular and cardiovascular adverse effects, and the FDA’s black box warning, he has been prescribing more cautiously, but he does sometimes use atypical antipsychotics, as do other clinicians.

Behavioral symptoms, particularly physical aggression, can be devastating for both the patient and the caregivers, he explained. “With the increased awareness of risks of antipsychotics, there has been greater enthusiasm for identifying alternative compounds as well as how best to implement behavioral strategies. Unfortunately . . . there really is far less known about other medications, and what is known, doesn’t suggest there is a magic bullet,” Sultzer said. “If you want to base a treatment on known effects, antipsychotics are one of the better categories because there have been many clinical trials data looking at their efficacy and side effects.”

Sultzer believes “behavioral interventions can be as effective or more so in some cases than particular medicines, and should be considered in all cases. The challenge is how best to implement those behavioral interventions.”

Bottom-line, Sultzer said, is that the clinician must really understand the individual patient’s clinical circumstances and the potential for benefit from a particular treatment given his or her particular risk.

References:

References

1. Jeste DV, Blazer D, Casey D, et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology. 2008;33:957-970.
2. Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med. 2006;355: 1525-1538.
3. Sultzer DL, Davis SM, Tariot PN, et al. Clinical symptom responses to atypical antipsychotic medications in Alzheimer’s disease: phase 1 outcomes from the CATIE-AD effectiveness trial. Am J Psychiatry. 2008; 165:844-854.
4. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med. 2009;360:225-235.
5. Schneeweiss S, Avorn J. Antipsychotic agents and sudden cardiac death-how should we manage the risk? N Engl J Med. 2009;360:294-296.