Tamra Wade

The number of new cases of cancer diagnosed annually in the United States increased from approximately 1.2 million in 2000 to 1.5 million in 2009.

 In 2009, approximately 562,000 people lost their lives due to some form of cancer.

 These fi gures, although tragic, represent a signifi cant improvement in cancer survivability, as the number of persons diagnosed increased 21.2%, but the increase in mortality was 1.8%. When adjusting for overall population increases, the mortality rate actually declined. Early diagnosis, treatment, and the availability of more antineoplastic drugs have contributed to the decrease in mortality rate.

Cancer cells reproduce at an abnormally faster rate than normal cells due to a disorder in the DNA of the cell that essentially tells it to divide in order to survive.

 Cancer types are determined by the point of origin because the replicating cancer cells resemble those in the original organ. For example, if a patient’s non—small cell lung cancer metastasizes to the liver, the patient has lung cancer, not liver cancer.

More than 100 drugs are used as monotherapy, concomitant, and/or adjuvant therapy to treat several forms of cancer, with the treatment protocol dependent on the nature of the organ involved. One of the latest oncologic drug classes is antineoplastic enzyme inhibitors, which are less invasive than several other forms of cancer treatment and are available as oral agents.

Antineoplastic enzyme inhibitors are used as targeted systemic therapeutic drugs that work to interfere with cell communication and growth.

 More specifi cally, these oral medications target and kill cells in the process of reproducing themselves by either (1) blocking cell receptors and/or (2) blocking blood/oxygen supplies to the cell, preventing angiogenesis. If successful, the treatment prevents the proliferation of abnormal cell growth that can lead to cancer. Unfortunately, the drugs also may affect other normal cells that commonly reproduce quickly, including hair follicles, ovaries and testes, and the blood-forming organs.

The majority of drugs in the class are tyrosine kinase inhibitors that focus on certain types of abnormal tyrosine kinase protein receptors (which types depend on the organ involved). To gain maximum effect, antineoplastic drugs are commonly used in combination with other forms of drug therapy or procedures (see 

). Antineoplastic enzyme inhibitors are approved by the US Food and Drug Administration (FDA) for several indications, including adjunct therapy uses. 

 provides a selected list of these indications.

The analysis is a retrospective study of 23.2 million members who had more than 240 million prescription claims. CVS Caremark’s computerized, deidentified database was used to study the utilization of antineoplastic enzyme inhibitors from January 1, 2008, through December 31, 2009. The population identified for the study consisted of members across a variety of plan sponsors including Medicaid, national and local employers, health plans, managed care organizations, insurance companies, unions, and government agencies located throughout the United States.

The members had claims in 2008 and 2009, categorized by generation with the following dates of birth: 1900-1925 (GI Generation); 1926-1945 (Silent Generation); 1946-1964 (Baby Boomers); 1965-1978 (Generation X); 1979-1990 (Generation Y); and 1991 to the present (Generation Z).

 In addition to categorizing utilizers by age band, we also separated metrics by sex.

In 2009, Gleevec had 48.0% of all antineoplastic enzyme inhibitor days supply (market share), followed by Tarceva, which had 22.2%. Afinitor, recently approved and available in April 2009, acquired 1.2% market share. Additionally, Sutent (+1.1%), Tasigna (+0.7%), and Sprycel (+0.5%) acquired market share, whereas Tarceva lost the greatest share at −2.0%, followed by Nexavar at −1.0% and Tykerb at −0.4%. The remaining drugs in the class had modest share changes due to low volumes (

According to the American Cancer Society, the estimated number of people diagnosed with cancer increased more than 21% between 2000 and 2009.

 More males were diagnosed than females both years. Males continue to have a higher ratio of new cases to death than females (

The National Institutes of Health estimated 11 million Americans with a history of cancer were alive, either cancer free or still undergoing treatment in 2006.

 Males have a higher lifetime risk of developing some type of cancer (1 in 2 people) than females (1 in 3 people). The majority (77%) of cancers are diagnosed in persons age 55 years and older.

) provides the 2009 average percentage of total utilizers, utilization (as a percentage of total days supply), and total cost per utilizer for antineoplastic enzyme inhibitors by generation and gender. The Baby Boomers and Silent Generation represented more than 85% of the total utilizers.

The average annual total cost per utilizer was $21,722 for females and $24,459 for males. Combined, Baby Boomers and the Silent Generation accounted for 85.1% of the total spending for this class.

From 2008 to 2009, gross cost per day figures increased by 14%, led by Gleevec, which had a 14.7% increase to $129.48. Tarceva, Sutent, and Nexavar also had gross cost per day increases of 8.2%, 5.9%, and 13.7%, respectively (

). Tasigna (not shown in Figure 2) had the highest gross cost per day at $200.56, but claim volumes were comparatively low.

) compares 2008 and 2009 utilization trends by both claims and days supply. Days supply varied by drug and was based on dosing (specifi c to cancer type) and patient demographics.

Antineoplastic enzyme inhibitors had a 19.0% gross trend, driven primarily by a 14.0% gross cost per day trend; utilization (days supply) increased 4.4% on a per member per month (PMPM) basis. Cost comparisons were not done because each drug in this class has a different purpose/subset of approved indications for a variety of conditions. However, the change for each drug was evaluated year over year. Only 1 of the primary drugs in this class, Tykerb, had a decrease (−4.2%) in gross cost per day in 2009. The remaining drugs had signifi cant year-over-year price inflation and contributed to the 14.0% year-over-year increase in gross cost per day driving the gross trend to 19.0%.

Gleevec had the largest increase in the number of prescription claims and a 4.8% increase in days supply PMPM. Nexavar lost the greatest number of claims and had a decrease of 10.2% in days supply PMPM. Gleevec utilization growth combined with a 14.7% gross cost per day increase acted as the primary driver of trend for the class, while Nexavar and Tarceva declines acted to moderate costs.

In November 2009, Votrient received approval from the FDA for advanced renal cell carcinoma. Uptake has been very low and metrics were not evaluated. Although many new development drugs are in the pipeline, there is no guarantee that the FDA will approve these drugs.

Although antineoplastic enzyme inhibitors are very costly and currently have no generic availability, these agents have greater tolerability and ease of administration (oral), and cause less intense reactions than many other cancer therapies. In addition, the aging of the Baby Boomers with their focus on wellness combined with early diagnosis likely will result in continued increases in the number of cancer cases being diagnosed and treated, therefore driving cost trends.

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Increases in the number of cancer cases being diagnosed and treated likely will drive cost trends for antineoplastic enzyme inhibitors.

Antineoplastic Enzyme Inhibitor Drug Trend Utilization in the United States

The proportion of Americans diagnosed with Alzheimer’s disease (AD) is projected to increase almost 2-fold over the next couple of decades due to size of the Baby Boom generation compared with the total US population. As a result, overall drug costs are likely to increase substantially over the same period. The impact on society and the nation’s healthcare system will be substantial. 

Alzheimer’s disease is characterized by progressive loss of memory, cognitive thinking, and motor skills. Noticeable symptoms commonly begin with signs of mild cognitive impairment progressing to severe dementia, usually leading to death within 8 to 10 years of diagnosis.1 The mental and physical effects of AD are devastating for patients as well as family members. Upon receiving the diagnosis, patients often suffer from depression and/or anxiety.2 As symptoms related to the disease become progressively more severe, patients not only have progressive cognitive dysfunction, but many also become highly combative. During this stage of the disease, managing patient behavior becomes increasingly difficult, often requiring several forms of treatment. As the patient progresses through the stages of the disease, simple life functions require caregiver assistance and can produce significant pressure and emotional stress on the provider. 

Care for patients receiving Alzheimer’s drug therapy (ADT) also can become financially burdensome because treatment, including medication, is very expensive. In addition to treatment of common conditions related to aging, such as high cholesterol and high blood pressure, patients receiving ADT may benefit from treatment of comorbid depression with antidepressants. Benzodiazepines occasionally have a role in treating patients with prominent anxiety, or they can be used on an as-needed basis for patients with infrequent episodes of agitation, although their effect is modest. Adverse effects from benzodiazepines include sedation, worsening cognition, delirium, increased risk of falls, and worsening of breathing disorders.2 Antipsychotic medications are prescribed by some physicians to treat aggression and agitation as well as severe or debilitating hallucinations and delusions. Neither typical nor atypical antipsychotics are approved by the US Food and Drug Administration (FDA) to treat psychosis in elderly demented patients. Both have a black box warning in their labeling that warns of an increased risk of death in this patient population. 

In addition to medications, AD patients may benefit from nonpharmacologic and behavioral therapy. In some cases, patients also may require supervision in a managed care facility to control behaviors and ensure patient safety. Others may find it more beneficial to use a comprehensive disease management program. 

Currently, there is no cure for AD or treatment for the reversal of dementia, and scientists do not know exactly what causes the disease. Several drugs are available to treat symptoms; however, efficacy is commonly short-lived and varies from person to person. Although a cure is not expected in the near future, researchers believe substantial progress has been made in identifying potential causes and biomarkers as well as in diagnosing the disease. There also is significant research on the prevention of AD. 

CVS Caremark conducted an AD drug utilization study to identify prevalence, concomitant therapy, drug trend cost, and utilization patterns by demographic groups. 

The analysis is a retrospective study and was conducted using 571.3 million prescription claims from CVS Caremark’s computerized database. The population identified for the study consisted of 29.4 million members across funded benefit prescription plans administered by CVS Caremark. The plan sponsors included Medicaid, national and local employers, health plans, managed care organizations, insurance companies, unions, and government agencies located throughout the United States with prescription claims for all months between January 1, 2008, and December 31, 2008. Members were categorized by generation with the following age bands: 83 years and older (GI generation), 63 to 82 years (Silent generation), 44 to 62 years (Baby Boom), and 30 to 43 years (Generation X).4 Utilization figures were based on days supply, and gross cost figures (which includes both plan sponsor and member contributions) were reported on a per member per month basis.

Alzheimer’s disease, which is the accretion of amyloid plaques and neurofibrillary tangles in the brain, was the seventh leading cause of death in the United States for 2006.5,6 It is believed these buildups cause nerve cell death, resulting in progressive cognitive dysfunction. Symptoms usually first appear at age 60 years, but the rare early-onset form of the disease may appear as early as age 30.1 The disease usually causes dementia and is diagnosed using family history, brain scans, and neurologic and neuropsychologic tests, but can be confirmed only at autopsy. 

There are several nontreatable causes of dementia, primarily including AD, vascular disease, Lewy body disease, and Parkinson’s disease. Alzheimer’s disease is the most common form in individuals over the age of 65 years, accounting for approximately 60% of cases.7 Vascular disease accounts for up to 20% of dementia cases commonly associated with occurrence of a stroke.1 Multiple sclerosis also has been associated with dementia. Multiple sclerosis is a demyelination disease of the central nervous system (CNS) that commonly leads to inflammatory and atrophic brain pathology, often causing cognitive impairment.

Current prevalence estimates range from 2.4 million9 to as many as 5.3 million10 Americans suffering from AD. The variability in the range of estimates is likely partially due to the difference in tracking methodologies3,8 combined with the difficulty of providing an accurate diagnosis. Globally, prevalence is estimated at approximately 27 million people.11 More than 90% of those diagnosed with the disease are 64 years of age or older, and AD is more likely to affect women. 

All drugs in the AD therapeutic class work to slow the worsening of symptoms of the disease, but do not stop brain cell death3 (Table 1). 

It is believed that acetylcholinesterase inhibitors including Aricept (donepezil hydrochloride), Exelon (rivastigmine tartrate), and Razadyne (galantamine hydrobromide) work to prevent the breakdown of the acetylcholine chemical in the brain. Namenda (memantine hydrochloride), a N-methyl-d-aspartate receptor antagonist, works to control a different chemical named glutamate.12 Because Namenda has a different mechanism of action for treatment, the drug often is used in combination with 1 of the other 3 drugs. Drug efficacy is relatively short-lived, usually lasting for only a few months to a few years. 

Patient psychiatric management procedures and tasks are utilized to maximize patient functionality and enhance the safety and comfort of the patient and family. The American Psychiatric Association (APA) has outlined guidelines for the treatment of AD patients. Once a patient has been evaluated using a battery of tests and diagnosed, a treatment standard of practice may include the following elements for mildly, moderately, and severely impaired patients. 

Three FDA-approved (Table 1) acetylcholinesterase inhibitors are used for the treatment of cognitive impairment (ie, Aricept, Exelon, Razadyne). Additionally, psychologic evaluations commonly follow to determine potential suicidality, mood, and/or depression symptoms. Depression is relatively common, particularly after the initial diagnosis, and may require antidepressant/antianxiety drug therapy. 

Concomitant utilization of Namenda is currently recommended during this phase to delay the progression of symptoms. Patients in this phase may show significant signs of agitation and combativeness toward caregivers in addition to hallucinations, delusions, and/or depression requiring additional treatment, including antipsychotics.2,13 

The 2007 APA guidelines suggest that if psychosis and agitation symptoms do not cause any significant danger or distress to the patient or others, such symptoms are best treated with environmental measures including reassurance and redirection. Behavioral measures also may be helpful for agitation if environmental measures are unsuccessful. If the behaviors are particularly dangerous or distressing, then the symptoms may be treated judiciously with antipsychotics, with the families informed of the relative risks and benefits, particularly the risk of mortality. 

Patients in this stage are normally completely dependent on others to complete basic life functions, including eating, bathing, and using the restroom. Aricept is the only cholinesterase inhibitor indicated to treat severe AD, and this drug is commonly utilized with Namenda.2 

The AD pipeline is, at present, both extensive and diverse. Drug development for AD has become substantially more focused as researchers continue to gain a better understanding of the disease. In 2000, acetylcholinesterase inhibitors, cholinergic agonists, neurotrophic factors, and anti-inflammatory agents formed the bulk of the late-stage pipeline. In 2009, a number of molecules were focused on beta-amyloid deposition and several others targeted tau protein formation. Additionally, several prospective agents are intended to protect neurons from degeneration. 14 Clinical trials have had mixed results. For example, a recent late-stage trial of a gamma-secretase modulator showed it did not prevent AD progression.15 

Despite the need for disease-modifying therapies, it is unlikely that a treatment will be developed in the next 10 years that completely halts or reverses progression of the disease. As a result, there will be continued demand for drugs that offer better symptomatic relief. Several of these also are in the nearterm pipeline, including transdermal and sustained-release reformulations. 

According to a recent report, more than a half-dozen investigational drug candidates are in late-stage development for the treatment of AD.14 Their launch is either projected for or may be reasonably expected to occur in the next few years. Recently approved, Aricept ODT (orally disintegrating tablet) is anticipated to have a generic alternative available in late 2010, and an Exelon (oral) generic is expected in 2012. 

There is a direct correlation between age and increased risk of AD. According to metrics from this study, once a person becomes age 84 years or older, the likelihood of being on AD drug therapy almost quadruples (Table 2). 

In 2008, approximately 1 in every 1000 baby boomers, 3% of those in the Silent generation, and more than 11% of those in the GI generation were utilizing an AD drug therapy. 

Results indicate 63.9% of overall utilizers were female and 36.1% male. The delta was much smaller for the Baby Boom generation (53.0% female) but widened dramatically as patients got older. Among utilizers age 84 years and older, 71.0% were female. Women have a longer average life span, which contributes to a higher relative risk of developing dementia and/or AD. However, AD is slightly more common in women16 (Figure 1). 

The Alzheimer’s Association estimates approximately 1 in 100 women at age 65 will develop dementia in their lifetime. By age 75, this figure increases to approximately 7 in 100 women. By the age of 85 the figure increases to more than 20 in every 100 women.8 

Aricept dominated the AD market with 53.6% of claims, followed by Namenda at 33.3%, and Exelon at 7.9%. Little change is expected over the next 10 to 12 months until the anticipated launch of Aricept ODT generic, expected in late 2010, which will likely have a significant impact on the class market shares and costs (Figure 2). 

As previously mentioned, Namenda is commonly utilized as both monotherapy and in conjunction with another AD drug. To provide another perspective on individual drug utilization, we determined how many AD patients utilized each drug by name. Results were as follows: 71.7% of patients used Aricept, 43.3% used Namenda, and 12.5% used Exelon. 

ADT patients’ overall annualized total drug cost was greater than that of non-ADT patients. The average annual total drug cost for a Silent generation member without AD was $2381 compared with $5268 for a Silent generation member with AD. A significant portion of the additional cost was due to concomitant drug therapy associated with the condition (Figure 3). 

Patients with AD often are subject to bronchial, cardiovascular, and other conditions associated with aging. In most cases, these conditions require additional drug treatment. Fortunately, many of the drugs used to treat these conditions are dispensed as generics, helping to moderate costs. As previously discussed, some AD drug utilizers have not been diagnosed with AD. Instead, many have other diseases, including multiple sclerosis, Parkinson’s disease, and Lewy body disease. The specialty drugs used to treat those conditions are very expensive. 

Of the top 10 drugs (by gross cost) used concomitantly with AD medications, 4 were atypical antipsychotics and 1 was a selective serotonin reuptake inhibitor (Table 3). The proton pump inhibitors Nexium and Prevacid were ranked 6th and 7th and at the time of the study were available as branded drugs. 

The symptoms/effects of AD require substantial caregiver responsibility. Additionally, the rapid progression of the disease and its symptoms increases the level of difficulty in providing care. Metrics obtained from the CVS Caremark study helped demonstrate the depth of the effect AD has on patients. Foremost, these patients have a large degree of concomitant drug utilization. Not only do they require common disease-related medications, but many also take antidepressants, antianxiety agents, or antipsychotic medication in addition to AD drugs. In addition to the clinical aspects of treatment and difficulty in providing care, AD patients’ overall drug costs are staggering. 

The FDA has not approved the use of antipsychotic drugs (typical or atypical) for treatment of elderly patients with dementia-related psychosis. In 2008, the FDA notified healthcare professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementiarelated psychosis. Although the current guidelines issued by the APA do not indicate removing antipsychotics as therapy, they recommend that these medications be used with caution and at the lowest effective dosage after considering the risks of not treating the psychiatric symptoms. 

The likelihood of developing AD increases with age. As people get older, they become more likely to be in the latter stages of the disease, often requiring more behavior management. 

In addition to drugs used to treat diseases commonly seen in the elderly, AD patients’ drug regimens also may include multiple CNS-related medications to help manage symptoms that are distressing to both the patient and the caregiver. Compounded by year-over-year increased utilization and price inflation, the high degree of concomitant drug use contributes to increasing yearover- year drug spending. Availability of a generic version of Aricept ODT in 2010 and Exelon in 2012 could moderate future costs. 

Existing pharmacologic therapies provide a degree of symptomatic relief for some patients; however, responses vary widely, with efficacy often diminishing over time. No way has yet been shown to slow or reverse the clinical progression of the disease. Although AD drug efficacy is less than optimal, any degree of patient relief is highly desirable. The AD drug pipeline appears relatively rich in prospects, many of which have targeted the root cause of the disease as it is currently understood. However, none of these drugs have yet proven their safety and efficacy. 

What is currently known about AD is that it is an exceptionally debilitating, costly illness without a cure that results in substantial caregiver burden. Experts believe the number of persons diagnosed with AD may almost double within 20 years. The Centers for Disease Control and Prevention notes: 

The United States is on the brink of a longevity revolution. By 2030, the proportion of the US population aged 65 and older will double to approximately 71 million older adults, or 1 in every 5 Americans. The farreaching implications of the increasing number of older Americans and their growing diversity will include unprecedented demands on public health, aging services, and the nation’s healthcare system.

The proportion of Americans diagnosed with Alzheimer's disease (AD) is projected to increase almost 2-fold over the next couple of decades due to size of the Baby Boom generation compared with the total US population.