According to market data cited in Part 1 of this report (Pharmaceutical Commerce, June, p. 1), antipsychotics are the single-largest therapeutic class in the market today, and antidepressants are one of the fastest-growing. Balanced against these positive trends are the problems of serious side effects for many of the products, necessitating a steady stream of new warnings and “black box” labels. Add to this the fact that CNS drugs are frequently prescribed off-label—and by a growing number of healthcare providers besides psychiatrists—and the risks for biopharma companies grow higher.
All these trends—plus a few more—are even more prominent when young patients, or the elderly, are being prescribed CNS drugs. Advocates agree that when used judiciously, antipsychotics and antidepressants can and do provide welcome relief for strong, healthy adult patients. However, the question of whether or not these strong medications are appropriate for use in children and adolescents, and among more frail older adults, remains the subject of intense debate. Despite the fact that the vast majority of antipsychotics and antidepressants do not have FDA approval for use by children or for older adults (with dementia); the off-label use of both classes of drugs has skyrocketed in recent years.
Proponents argue that the dearth of suitable, FDA-approved alternatives to treat the vast array of behavioral and psychiatric problems that arise in the young and old leaves practitioners with few alternatives but to use existing antidepressants and antipsychotics off-label. Said one physician: Withholding proven psychiatric drugs from a child who needs them can be likened to “seeing someone dying and not giving them CPR.” However, critics contend that the laundry list of potentially life-threatening side effects makes their use in these vulnerable sub-populations especially troubling.
Further complicating an already tangled medical and drug-marketing environment, mental health professionals are still weighing the outcomes of the landmark CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study, a longterm outcomes-based study sponsored by the National Institutes of Mental Health. When the first results were published in 2005, the surprising implication was that the newer classes of “atypical” antipsychotics seemed to be no less prone to side effects, or are effective, than the older “typical” antipsychotics that they were intended to replace.
Evidence of the trends in prescribing CNS drugs to young and old patients can be seen in the latest (2008) data from pharmacy benefits manager (PBM) Medco Health Solutions (Franklin Lakes, NJ). The use of newer atypical antipsychotics has increased across all age groups, and with the exception of the youngest children (age 0-9), antidepressants use has also grown across all age groups.
When it comes to antidepressants, the Medco prevalence data confirms that antidepressant use has also been on the rise across all age segments except for the youngest pediatric sub-population (age 0-9). This suggests that the black box warnings have helped to rein in the use of antidepressants among the youngest patients over the past few years.
The trends revealed in Medco’s analysis are based on an annual probability sample of 2.1 to 2.9 million insured in the sample years, which is a statistically relevant sampling of Medco’s 62 million insureds. “Considering that Medco provide pharmacy benefits for one in five Americans, and fills roughly 600 million prescriptions per year for its 62 million members, these data provide useful insight into usage patterns nationwide,” says Jennifer Leone Luddy, a public affairs officer at Medco Health Solutions (Franklin Lakes, NJ).
“When it comes to the off-label use of these drugs among older adults, it’s not because all of these geriatric patients have schizophrenia or clinical depression; it’s because they have underlying cognitive problems (such as dementia) with related behavioral problems that cannot be managed optimally without pharmacological intervention,” says Barney Spivack, MD, medical director at LifeCare (Shelton, CT).
As of last summer, only three antipsychotics had received FDA approval for use in children — the generic typical antipsychotics Haldol (haloperidol) and Mellaril (thioridazine), and the newer atypical agent Risperdal (risperidone) from Johnson and Johnson subsidiary Janssen. Under the expanded FDA approval, the company can now explicitly market Risperdal for use in children 13 to 17 with schizophrenia, and for short-term use in children ages 10 to 17 with bipolar disorder.
However, Risperdal is still not approved for treating attention deficit disorders, and its side effects (including substantial weight gain, metabolic disorders and muscular tics) are “too profound to justify its use in treating such disorders,” according to a panel of federal drug experts, as reported in the New York Times on November 18, 2008. The panelists said the current black box warnings were not sufficient, and stated that their concerns applied not just to Risperdal, but to other medicines in its class, including Zyprexa, Seroquel, Abilify and Geodon, as well.
FDA has said that the agency could do little to fix the problem, since it does not prohibit doctors from prescribing any FDA-approved drugs for off-label uses. Rather, the onus falls to medical specialty societies and drug companies to do a better job educating doctors about the side effects of these potent drugs.
While FDA does not limit physicians’ ability to prescribe drugs off-label as they see fit (based on the available evidenced-based data), the agency does prohibit drug companies from explicitly marketing any drugs for indications or patient populations that are beyond the scope of the drug’s FDA approval.
In part because of the severity of the side effects associated with today’s antipsychotics and antidepressants, marketing outreach associated with these two classes of psychiatric drugs has come under particularly tight scrutiny in recent years, and several recent landmark judicial settlements now serve as a cautionary tale for makers of these drugs.
For instance, in January, Eli Lilly (Indianapolis, Ind.) agreed to pay $1.42 billion to settle federal criminal charges that the company illegally marketed its atypical antipsychotic drug Zyprexa (olanzapine) for the off-label treatment of psychoses and behavioral problems in older patients with Alzheimer’s disease and other dementia. The lawsuits also claim that the company knew Zyprexa was dangerous and unsafe but failed to take the necessary steps to inform patients or prescribers.
Similarly, in October 2007, Bristol-Myers Squibb agreed to pay $515 million to settle allegations of off-label marketing, kickbacks paid to physicians, and price-fixing schemes related to its atypical antipsychotic Abilify (aripiprazole). Six BMS whistleblowers brought suit against the company and its affiliate Apothecon, Inc., in Massachusetts and Florida, alleging that BMS actively promoted off-label use of the drug, and rewarded physicians for prescribing it. Between 2000 and 2005, prosecutors say the company maintained a sales force that specifically marketed the drug to nursing home, long-term care facilities, pediatric psychiatrists and other pediatric specialists.
Meanwhile, according to published reports, AstraZeneca currently has more than 9,000 suits pending related to its atypical antipsychotic Seroquel (quetiapine) — today’s best-selling antipsychotic. Plaintiffs allege that the company knew as early as 2000 that Seroquel caused diabetes, weight gain and other health problems, but failed to adequately warn patients and doctors. And at least four states (Pennsylvania, Montana, Arkansas and South Carolina) are also suing AstraZeneca, claiming that the company aggressively marketed and promoted Seroquel for off-label use that was beyond its FDA-approved indications during the period in question.
Life after CATIE
Billed as wonder drugs when they entered clinical use in the mid-1990s, the atypical antipsychotics were long believed to be more effective and to have significantly fewer side effects compared to the older typical antipsychotics — and were aggressively marketed as such. As a result, the newer atypicals quickly gained a foothold, as a safer, more-effective alternative to the older, typical antipsychotics. These improvements, and the fact that the newer atypicals did not cause the same tics, muscular rigidity, Parkinson’s-like tremors and cognitive impairment that are the hallmark of many of the earlier typical antipsychotics helped fuel rapid adoption, and today the newer, branded second-generation atypicals represent at least 90% of the current market, even though they cost more than the older antipsychotics, most of which are now available as generics.
In 2005, the first of many study results from the government-funded CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) trials were published, and since then, each subsequent publication of the phased results has, in effect, chipped away a little bit more of the foundation on which these newer atypicals have historically been marketed.
Today, CATIE continues to cast doubt on this prevailing wisdom, by suggesting that the newer drugs were no better than older drugs that sell for less, and that many of them had more severe adverse effects than had once been believed.
Specifically, the landmark CATIE study provided the first and largest ever head-to-head comparison of the leading antipsychotics —Risperdal (risperidone) from Johnson and Johnson division Janssen, Zyprexa (olanzapine) from Eli Lilly, Seroquel (quetiapine) from AstraZeneca, and Geodon (ziprasidone) from Pfizer — against one another, and against several of the older typical antipsychotics. To the consternation of many drug makers, CATIE proved that the newer atypicals had much more variable response than had been widely advertised, and thus they could not be differentiated as unequivocally (either from each other, or from the older typical counterparts) as their makers had long claimed.
Perhaps more important, CATIE provided evidence-based validation that the newer atypical antipsychotics cause severe, life-threatening side effects for a significant number of patients. Specifically, CATIE showed that the newer atypical antipsychotics have side effect profiles that are severe enough to cause premature discontinuation of use by patient — thus limiting their utility as a long-term treatment option.
Similarly, a more recent analysis of CATIE data, July 1, 2008 in the British Journal of Psychiatry, showed that while antipsychotic medications can reduce the risk of violence among people with schizophrenia, the newer atypical antipsychotics are not more effective in doing so. And, another NIMH-funded study (the six-year, multi-site Treatment of Early Onset Schizophrenia Study, or TEOSS), published in September 2008 in the American Journal of Psychiatry, found that two of the newer atypical antipsychotic medications (Zyprexa and Risperdal) were no more effective than an older conventional antipsychotic (Moban/molindone) in treating child and adolescent schizophrenia and may lead to more metabolic side effects.
Since 2005, CATIE has proven to be a game changer for the entire class of antipsychotics, because it has undermined the long-standing claims of inherent superiority that makers of the newer, atypical antipsychotics had long relied on as the backbone of their marketing campaigns, and forced makers of all of the newer, atypical antipsychotics to refine their marketing messaging in recent years.
CATIE also showed that Novartis’ Clozaril (clozapine), the oldest of the atypical antipsychotics (which is now available as a generic), outperformed all of the newer, more expensive branded atypicals in the study, in terms of efficacy, which was defined in this study as time to discontinuation, or “how long patients stayed on the drug.” Specifically, Clozaril showed a nearly a three-fold increase in time until drug discontinuation compared with the three newer antipsychotics (Risperdal, Seqoquel and Zyprexa), and efficacy outcomes were consistent with the time-to-discontinuation measure.
While insurers and other payors may have been happy to learn from CATIE that a cheaper generic could outperform the more costly branded agents in the same class, the results were not so clear cut, because despite its apparent efficacy advantages, clozapine has its own side effects burden, which has historically limited its use.
According to NIMH: “Not all patients can or want to take clozapine, because it may cause serious side effects in some people.” These include a potentially fatal inflammation of the heart muscle, and agranulocytosis, which is a dangerous drop in levels of disease-fighting white blood cells that are part of the immune system. As a result, patients taking clozapine require rigorous monitoring while taking the drug.
Which might be part of the answer to why, despite CATIE, the newer atypicals are far more frequently prescribed than the older typicals, or clozapine. IMS Health data show that the older drugs prescribing rates have hardly budged between 2004 and 2008; collectively the generics chlorpromazine, haloperidol and clozapine represented 8.0% of the 2008 market, down from 2004’s 8.6%.
One important outcome of CATIE is that the study verified that the potential side effects of all antipsychotic drugs are severe enough to require diligent ongoing monitoring, including recommended bloodwork. “As long as psychotropic medications were considered relatively free of side effects, psychiatrists could practice in settings appropriate to other mental health counselors. However, medication treatment with high side effect burden demand clinical settings that are capable of detecting and managing serious side effects,” wrote Dr. Carol Tamminga, a leading schizophrenia researcher, in an editorial that accompanied the two CATIE trial reports (American Journal of Psychiatry, April 2006, Vol. 163:563-565). “Clinicians will need to have systems for the effective monitoring of drug side effects to maintain and promote physical health among patients, as well as psychiatric health.”
However, despite the clarion call for more rigorous monitoring — and recommendations that have been in place for years from the American Diabetes Assn., American Psychiatric Assn., American Assn. of Clinical Endocrinologists, and the North American Assn. for the Study of Obesity — the monitoring of glucose and lipid levels among patients using atypical antipsychotics still falls far below the recommended guidelines, according to a recent study at the Washington University School of Medicine, led by Dan W. Haupt, MD, an investigator at the National Alliance for Research on Schizophrenia and Depression (NARSAD; Great Neck, NY), which was published January 15, 2009, in the American Journal of Psychiatry.
The study showed that by 2006, just 10% of patients receive lipid monitoring and 20% received glucose monitoring. “Many psychiatrists were not trained to consider the effects of mental illness and treatment of the whole patient, and many practice in environments that are physically separated from the rest of the healthcare system,” said Dr. Haupt, at the time of the release. He views this as a missed opportunity to reduce the impact of medical comorbidities in patients, which, according to the Institute of Medicine, should be anticipated and included in treatment planning.
Closing the information gap
Drug makers can help to close this gap. While pharma marketers must find a delicate balance — in order to stay on the right side of the demarcation between appropriate and inappropriate outreach — there’s plenty they can do to encourage evidenced-based use ongoing sales of their products, especially for the clinically appropriate off-label use.
“While it’s a mistake for drug companies to proactively go after these unapproved indications, it’s perfectly appropriate for drug companies to respond to professional requests for support, information, studies and so on, to promote the safest, most appropriate use of these drugs,” says F. Randy Vogenberg, RPh, PhD, principal for the benefits and training consultancy Institute for Integrated Healthcare (Sharon, MA).
Meanwhile, Medco is working to improve drug education and safety in these and other drug classes, through the use of “advanced-practice” Therapeutic Resource Centers (TRC) that Medco operates as part of its mail-order pharmacy system. Today, Medco’s TRCs are organized by specialty (such as diabetes, cancer, heart disease, asthma other pulmonary diseases, psychiatry, neurology, and more), and employ more than 1,100 “specialist pharmacists” who handle the majority of Medco prescription orders related to those categories.
Despite the availability of numerous antipsychotics and antidepressants that have significantly improved the lives of many patients, significant treatment gaps remain, and the troubling side effect profiles of both classes of CNS drugs underscore the need for improved therapeutic options. Similarly the need for faster-acting antidepressants is “a priority,” according to NIMH, to relieve symptoms of the disorder in hours or days, instead of weeks or months it takes for current antidepressants to work.
“Unfortunately, many of the new drug announcements lately in this space have really focused on different dosages or repackaging — there have been very few advances in recent years,” says Spivack. “Although currently available drugs can be used more effectively, we will all benefit from new compounds targeting new mechanisms of action, and drugs with greater efficacy, safety and tolerability that may be developed to treat patients who do not find relief using current agents.”
“Anything new will need to have a significant benefit over the current generic offerings, as the era of ‘me-too medications’ is over,” says Richard Stefanacci, director of the Institute for Geriatric Studies at the University of the Sciences in Philadelphia. “Only those medications that have significant — and I mean significant — benefit will even gain approval going forward.” PC