treating allergic asthma with omalizumab

Dis Manage Health Outcomes 2007; 15 (3): 165-179REVIEW ARTICLE 1173-8790/07/0003-0165/$44.95/0

© 2007 Adis Data Information BV. All rights reserved.

Treating Allergic Asthma with OmalizumabPaul P. Belliveau and Monina R. Lahoz

School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, Worcester, Massachusetts, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1651. Disease Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

1.1 Pathophysiology and Omalizumab Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1661.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1671.3 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

1.3.1 Asthma Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1671.3.2 Asthma Severity Categorization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1671.3.3 Economic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1681.3.4 Asthma Severity and Healthcare Resource Utilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1681.3.5 Health-Related Quality-of-Life (QOL) Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

2. Overview of Current Management Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1693. Omalizumab Clinical Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

3.1 Safety and Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1704. Omalizumab Humanistic Outcomes: Asthma-Related QOL and Perceptions of Treatment Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . 1715. Omalizumab Economic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

5.1 Drug Acquisition Process and Coverage/Reimbursement in the US . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1725.2 Drug Product Cost and Administration Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1725.3 Resource Utilization and Pharmacoeconomic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

6. Managed Care Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1746.1 Considerations for Managed Care Organizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1746.2 Proposed Criteria for Omalizumab Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

6.2.1 Predicting Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1766.2.2 Selection Criteria for Omalizumab Prescribing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

Asthma is a chronic condition with characteristics that make it an ideal target for interventions used withinAbstractdisease state management in managed care settings. It affects a substantial population of patients and imposes anincreasingly significant global societal burden. Despite the availability of many asthma medications and easilyaccessed publications providing step-wise guidance for asthma management, there are still patients whosecondition is not well controlled. Hence, there is a continuing need for unique treatment options. Omalizumab is asubcutaneously administered monoclonal anti-IgE antibody that reduces free IgE concentrations and promotesdown-regulation of IgE receptors on basophils. This relatively new pharmacologic intervention has been shownto reduce inhaled corticosteroid (ICS) and rescue medication requirements, and improve asthma control andquality of life in patients with moderate to severe allergic asthma with disease poorly controlled by ICSs.However, because of its high cost relative to other asthma drug therapies, health plans/payers must ensure thatcriteria for its use are clearly identified so as to target patients who will most likely benefit from such therapy.Omalizumab may need to be restricted to asthma patients with severe persistent allergy who are categorized as‘high risk’ (e.g. patients with a recent history of frequent intubations, emergency room visits, overnighthospitalizations, or intensive care unit admissions for asthma exacerbations) who remain symptomatic despiteappropriate maximal maintenance therapy for the severity of their disease. If restricted to this narrowly defined

166 Belliveau & Lahoz

population of patients with allergic asthma, cost-of-care studies suggest that the high cost of this product couldbe offset by savings resulting from the less frequent use of high-intensity medical services for asthmaexacerbations.

Asthma is a condition with characteristics that make it an ideal 1. Disease Profiletarget for interventions used within disease state management inmanaged care settings.[1] It is a chronic condition that affects a

1.1 Pathophysiology and Omalizumab Mechanismsubstantial population of patients and imposes a significant burden of Actionin terms of treatment costs, productivity losses, and reduced quali-ty of life.[2-5] Additionally, the risk associated with treatment For patients whose exacerbations are associated with allergen

exposure, the following model can be used to help understand thefailures is high, particularly in terms of resource utilization.[2-5]

pathophysiology behind their disease and the role that omalizumabAsthma management also requires important patient self-caremay play in the treatment of patients with allergic asthma. Forefforts,[6,7] a characteristic identified by the Disease Managementthese patients, the model begins with exposure of an allergen toAssociation of America as necessary for a condition to be consid-antigen-presenting cells (macrophages, dendritic cells) that engulfered a good candidate for a disease management approach.[8]

the allergen, process it, and display a portion of the allergen on itsThe development and utilization of well referenced, evidence-

surface for presentation to T and Blymphocytes. This is followedbased prevention and management guidelines is one of the key

by T- and B-lymphocyte interactions that activate B lymphocytescomponents of the disease management approach.[8] This is partic-

and promote allergen-specific IgE production (figure 1).[20] IgEularly important for asthma care as there are numerous interven- binds to receptors (FcεRI) on basophils and mast cells (basophil-tions and drug treatment options available for prevention and like cells located in tissues).[21,22] Following subsequent antigenmanagement, prompting the development of authoritative guide- exposure, cross linking of the antigen by multiple FcεRI-boundlines that assist clinicians with the care of individual asthmatic IgE molecules triggers the release of preformed inflammatorypatients.[6,7,9] Although these guidelines include many drug ther- mediators and the synthesis and release of newly generatedapy options, some of the available agents focus only on symptom mediators and cytokines from these cells. Released mediatorsrelief, others are non-specific in their mechanism of action, and initiate an inflammatory response, resulting in bronchial mucosalnone provide relief in all patients.[6,7,10] Hence, there is a clear need edema, mucous production, and bronchial smooth musclefor new interventions to improve the care of asthmatic patients.[11] spasm.[7,18,23,24] Although not all cases of asthma are clearly allergy

The subcutaneously administered monoclonal anti-human IgEantibody, omalizumab, is one of the more recent asthma treat-ments to be introduced into clinical practice. It provides clinicianswith an additional option for treating patients whose asthma isconsidered to be allergy induced. However, its high cost has raisedconcern about its cost effectiveness and prompted discussion ofhow to identify the best candidates for such therapy.[12-16] Thisreview is designed to address such concerns. The goal of thisreview is to provide an objective evaluation of omalizumab’sutility in the management of allergic asthma. Although a trulybalanced assessment of the impact of this therapy would addresseach component of the Economic, Clinical, and Humanistic Out-comes (ECHO) model,[17] several recent reviews provide detailedsummaries that include relevant clinical and humanistic outcomedata.[15,18,19] The current article will briefly highlight this informa-tion while focusing on the economic portion of this model andproviding patient selection guidance for managed care organiza-tions.

Basophil

FcεRI receptor

IgE moleculeFcεRI binding sites

APCT lymphocyte B lymphocyte

Omalizumab IgE

or

Fig. 1. Pathophysiology of allergic asthma and the action of omalizumab.After allergen exposure, the antigen-presenting cells (APC) process theantigen for presentation to the T lymphocyte, prompting interactions be-tween T and B lymphocytes that result in IgE production. IgE may bind tothe FcεRI receptor on a basophil. With subsequent allergen exposure, theallergen will be bound by IgE on the basophil, resulting in release ofinflammatory mediators and an allergic-asthma exacerbation. Omalizumabprevents the exacerbation by binding to IgE before it can bind to thebasophil (reproduced from Belliveau and Lahoz,[15] with permission).

© 2007 Adis Data Information BV. All rights reserved. Dis Manage Health Outcomes 2007; 15 (3)

Implications for Managed Care Organizations 167

related, it is accepted that atopy can play an etiologic role in its 1.3 Epidemiology

pathophysiology. Researchers reviewing this literature have esti-

mated that approximately 40% of asthma cases can be associated 1.3.1 Asthma Prevalencewith atopy (these associations neither prove causality nor establish Despite the inherent sources of inaccuracy (i.e. the lack of athat atopy actually drives asthma exacerbations in these pa- uniform objective diagnostic test, different interpretations oftients).[25] Additionally, atopy is one of the strongest currently symptoms and classifications of disease) in asthma prevalenceidentified predisposing factors for the development of asth- studies, cumulative reports consistently indicate that there is a

large burden of asthma worldwide. Furthermore, this is a burdenma.[7,26,27]

that is expected to grow by 100 million people by 2025, with theOmalizumab is a monoclonal anti-human IgE antibody thatincreasing westernization and urbanization of the world’s popula-binds circulating free human IgE, reducing the amount of free IgEtion.[39] Despite these projections, the care for such patients may inavailable for binding to cells and tissues.[28,29] As the reductions inpractice be improving in light of reports and cost trends detailing

free IgE promote a down regulation of FcεRI on basophils (figuredecreasing asthma-related hospitalizations and mortality in asth-

1),[30-32] there is also a concomitant decrease in the amount of freematic patients.[3,4,40] The Global Initiative for Asthma (GINA)

and basophil-bound IgE.[32-35] These actions and effects subse-estimates that approximately 300 million people in the world have

quently reduce the likelihood of antigen-induced basophil asthma, with large prevalence differences between countriesdegranulation.[32,36,37]

(range 1–18%).[6] Countries whose asthma prevalence rates wereconsistently among the highest in two of the largest standardizedinternational surveys to date (the International Study of Asthma1.2 Diagnosisand Allergies in Childhood [ISAAC] and the European Communi-ty Respiratory Health Survey [ECRHS]) include New Zealand andThe diagnosis of asthma typically involves review of a patient’sAustralia.[41-43] Asthma affects approximately 600 000 peoplesymptoms and pulmonary exam.[6] A clinical diagnosis may be(15% of adults and 20% of children) in New Zealand[44] and 2.2established by patient complaints of episodic breathlessness,million in Australia (10–12% of adults and 14–16% of chil-wheezing, cough, and chest tightness. Symptom correlation withdren).[45] In the US (another country found to have a high preva-

potential triggers or seasons and a family history of asthma orlence rate), the 2004 National Health Interview Survey of people

atopy may also assist in the diagnosis. Patterns that are strongaged ≥18 years revealed that 9.9% (21.3 million) of people report-

clues include episodic/variable symptoms; precipitation by irri- ed having been diagnosed with asthma during their lifetime, andtants (e.g. smoke, fumes, strong smells) or exercise; worsening at 6.7% (14.4 million) of people reported that they still have asth-night; and a positive response to asthma therapy. As a result of the ma.[46] Among American children aged <18 years, an estimatedepisodic nature of the symptoms, physical examination may or 12.7% (8.9 million) have had asthma diagnosed at some time inmay not reveal wheezing with pulmonary auscultation. their lives, with the percentage increasing as age increases.[47]

Quantification of airflow limitation and airway responsiveness1.3.2 Asthma Severity Categorizationcan assist with the diagnosis of asthma.[6] Measures of airflowIn phase II of the ECRHS, the application of GINA asthmalimitation include the forced expiratory volume in 1 second

severity definitions revealed that 58% of the young adults sur-(FEV1) and the forced vital capacity (FVC), measured by spirome-veyed had intermittent asthma and 31% had moderate or severe

try during a forced expiratory maneuver, and the peak expiratorypersistent disease.[48] Australia and the US had the greatest per-

flow (PEF), measured via a PEF meter. Abnormalities in thesecentage of patients (approximately 40%) reporting at least ten

measurements and their reversibility with inhaled bronchodilatorexacerbations over the prior 12 months.[49] Separate studies of

administration may help confirm the asthma diagnosis. Addition- adults in these countries revealed that a large proportion of patientsally, these measurements and the pattern of the patient’s symptoms with asthma can be classified as having intermittent diseaseallow severity assessment during the initial evaluation prior to (32.9–35.9% of Australian adult patients and 34.2% of US adultstarting therapy. Although past guidelines have recommended that patients).[40,50] Moderate or severe persistent disease is reported intreatment be dictated by these asthma disease severity classifica- 28.0–35.6% of Australian adults with asthma and 43.1% of UStions,[7,27] recent iterations have emphasized that disease severity asthmatic adults. The majority of asthmatic children in each coun-be dictated by the intensity of treatment that is required to achieve try are considered to have the mildest category of diseaseadequate levels of asthma control.[6,9,38] (68.5–82.5% in Australia, and 59% in the US).[40,51]



In the AIRE (Asthma Insights and Reality in Europe) study, pharmaceuticals (37.3%) and hospitalizations (17.9%). More re-investigators graded asthma severity (as defined in the GINA cent data from 2000–1 revealed an annual cost of $Aus693 millionguidelines) based on patient interview responses to questions (54% attributable to pharmaceuticals, and 24% to hospitaliza-related to the pattern of their symptoms.[52] In both children and tions).[40] The total cost of asthma in Europe is approximatelyadults of all seven Western European countries studied, most €17.7 billion ($US21.7 billion) per year (year of values notpatients had disease that could be categorized as intermittent. In stated).[58] Of this, €7.9 billion ($US9.7 billion) is for direct coststhis study, children tended to have less severe disease (38.5–61.6% (€3.8 billion for outpatient care, €3.6 billion for anti-asthmaticin the intermittent category and 20.4–34.1% in the moderate or drugs, and €0.5 billion for inpatient care), and €9.8 billionsevere persistent categories) than adults (28.4–44.7% in the inter- ($US12 billion) is for indirect costs (such as those related tomittent category and 35–52.2% in the moderate or severe persis- impairment and productivity losses).[58]

tent categories).

1.3.4 Asthma Severity and Healthcare Resource Utilization1.3.3 Economic Considerations A large amount of healthcare resources are consumed by aDirect and indirect asthma costs remain considerable despite relatively small cohort of patients with difficult-to-treat asth-

data indicating shifts in cost burdens away from hospital-based ma.[53,56,58-60] It is estimated that 70% of patients with mild diseasecare, a finding that may reflect improvements in the care of account for only 20% of total asthma costs, while 10–20% ofasthmatic patients.[2-5,53] Using data from surveys conducted by the patients who have severe disease are responsible for approximate-National Center for Health Statistics, a US analysis reported the ly 50% of all costs.[58] US investigators have reported that as muchtotal cost of asthma was $US10.7 billion in 1994, a figure that was as 80% of direct asthma costs are consumed by <20% of asthmamore than twice the estimated cost of asthma 10 years earlier.[53,54]

patients (defined as ‘high-cost’ patients).[59] For such patients, theDirect medical costs (particularly costs related to hospitalizations

estimated direct annual cost per high-cost patient was $US2584and medications) accounted for the largest component (56.8%) of

compared with $US140 for other patients with asthma. In anotherasthma-related costs. Although hospital inpatient care represented

study, the direct annual average costs (adjusted to $US, 1998the largest direct medical component cost (44.6% of total direct

values) for patients who self-reported their asthma as mild, moder-costs) in 1985, medications were the largest in 1994 (40.1% of

ate, or severe were $US2646, $US4530, and $US12 813, respec-total direct costs), followed by hospital inpatient care (29.5% of

tively.[56] In this same study, disease severity also had an impact ontotal direct costs). In 1994, indirect costs of asthma accounted for

specific components of expenses: for patients with mild, moderate,43.2% of the total cost, the largest component being loss of work

and severe asthma, hospital admissions comprised 4%, 5%, and(44.6% of indirect costs). In a more recent report, 43.5% and

17% of total direct annual costs, respectively, and medication31.3% of total direct costs were due to medications and hospital-costs comprised 47%, 39%, and 19% of total direct annual costs,izations, respectively.[55] These trends were also described in anrespectively.analysis by Cisternas et al.[56] in a review of asthma patient data

Investigations outside the US reveal trends similar to thosederived from a group of community practitioners in northernreported within the US. In an investigation utilizing an indepen-California. In this study, direct medical and non-medical costsdent expert panel of French physicians to assess asthma severity inaccounted for 64.8% of asthma costs. Of these direct costs, 50%their patients, Godard et al.[61] reported significant differences inwere ascribed to pharmaceuticals and only 14.6% to hospitaliza-the direct treatment costs of patients with asthma, with greatertions. Indirect costs accounted for 35.2% of total costs, almost allcosts being observed in patients with more severe disease. In aof which were attributed to work/productivity losses.cross-sectional study performed in Spain, Serra-Batlles et al.[62]As observed with the US data, economic burden studies con-showed that a small number of asthmatic patients (14%) accountedducted in other countries also reveal a substantial burden associat-for a large portion of the total average annual asthma care costs.ed with asthma treatment. In New Zealand, the estimated total costTotal annual costs increased with increasing disease severity. Theof asthma per year in the late 1990s was approximately $NZ825annual cost per patient for those with moderate disease was almostmillion. Direct medical costs amounted to $NZ125 million, 40%1.8-fold higher than that of patients with mild disease; the cost perof which was attributed to medications. Indirect medical costspatient for severe asthmatics was 4.8-fold higher than that of mildamounted to $NZ700 million.[44] Data from Australia in 1989–90asthmatics. Consistent with these studies, reports on New Zealandrevealed total asthma costs of $Aus586 million, approximatelypatients indicate that the 10% of patients who have severe asthma55% of which were attributable to direct medical costs.[57] Theaccounted for 50% of the total costs.[63]largest direct medical component costs were related to



Disparities exist in the rates of asthma prevalence and asthma is well established that patients with asthma have a notable reduc-outcomes among segments of a given population. In Australia, tion in their quality of life (QOL),[67] particularly for patients withAboriginal and Torres Strait Islander people have higher rates of more severe categories of disease or who experience inadequatelyasthma prevalence than the general population. They, along with controlled symptoms.[68] A reduced QOL has been shown toadults living in rural or remote areas and people living in the most contribute to increased rates of healthcare utilization. In a health-socioeconomically disadvantaged areas, also have higher rates of related QOL (HR-QOL) survey of asthma patients in a healthhospitalization for asthma.[40] In the US, minority group children maintenance organization, Eisner et al.[69] reported that higherhave higher prevalence of asthma than non-Hispanic White chil- asthma-specific HR-QOL was associated with a decreased risk ofdren: prevalence rates for Puerto Rican children are 140% higher, asthma-related emergency department visits or hospitalizations,rates for non-Hispanic black children are 60% higher, and rates for and decreased asthma-related healthcare costs.American Indian or Alaska Native children are 25% higher. Com- Since conventional clinical measures of asthma are not com-pared with White children, Black children have a 260% higher rate plete descriptions of the functional impairments or improvementsof emergency department visits and a 250% higher hospitalization experienced in clinical trials,[70] instruments have been developedrate for asthma. Additionally, among minority children, Black and validated for evaluating asthma-related QOL outcomes inchildren were the least likely to be treated for asthma during clinical trials. One such tool is the Juniper Asthma Quality of Lifeambulatory care and in the emergency department.[64] Although Questionnaire (AQLQ), which comprises 32 items that representmany factors affect these patterns, there is good evidence for an

four domains (subscales): (i) activity limitation; (ii) emotions;environmental impact on asthma incidence and mortality as pa-

(iii) symptoms; and (iv) exposure to environmental stimuli.[71]

tients may experience greater asthma-inciting exposures to indoorThis tool allows for detection of minimal, moderate, and large

allergens (including dust mites, cockroaches, molds, and animalchanges in HR-QOL. It is the tool utilized for the omalizumab

dander) in economically disadvantaged areas.[65]

trials discussed in section 4.Improvements in the management of patients with the most

severe asthma could have a substantial impact on asthma care2. Overview of Current Management Strategiescosts. Cisternas et al.[56] concluded that a 5% shift of patients from

a severe to a moderate asthma classification would save approxi-Although pharmacological management of asthma can be ef-mately $US1.4 billion annually. As suggested by the inverse

fective in controlling patient symptoms, measures to prevent expo-relationship between the direct costs of hospitalizations and medi-sure to contributing etiological factors should also be em-cations reported by Cisternas et al.,[56] adequately managed asthmaployed.[6,9,27] Symptoms may be exacerbated by a variety of poten-is likely to reduce hospitalizations.[66] With improved medicationtially modifiable factors, such as exposure to allergens (mites,management, medication costs will probably increase, but the costdust, animal dander, fungus, pollen), pollutants (smoke), occupa-associated with hospitalization should decrease.tional irritants, food allergens, and medications with bronchospas-

1.3.5 Health-Related Quality-of-Life (QOL) Considerations tic pharmacological properties. Other potentially modifiable exac-erbating risk factors include obesity, emotional stress, rhinitis,As a result of the negative impact of asthma on a patient’ssinusitis, and gastroesophageal reflux disease.physical, psychological, and social well-being and functioning, it

Table I. Levels of asthma control[6]a

Symptom control measures Controlled all of the following: Partially controlled any of the following:

Daytime symptom frequency None or symptoms <2 times per week Symptoms >2 times per week

Activity limitations No limitations Any limitation

Nocturnal symptoms or awakenings None Any

Rescue reliever requirements None or symptoms <2 times per week >2 times per week

Objective lung function assessments Normal <80% of predicted or personal best(FEV1 or PEF)

Exacerbations None One or more per year

a A patient is considered to have an uncontrolled asthma week if they experience an exacerbation or if they meet three or more features of partiallycontrolled asthma in any week.

FEV1 = forced peak expiratory flow volume in 1 second; PEF = peak expiratory flow.



Short-actingβ-adrenoceptor

agonist (prn)

Long-actingβ-adrenoceptor agonist

Systemic corticosteriod

Omalizumab

Omalizumab


agonist (prn)

Low-dose ICS Low-dose ICS Medium/high-dose ICS Medium/high-dose ICS

Step 1 Step 2 Step 3 Step 4 Step 5


agonist (prn)


agonist (prn)


agonist (prn)

1

1



Fig. 2. Overview of preferred current management strategies for adult patients with asthma. Therapy recommendations adapted from the guidelinespublished by the Global Initiative for Asthma (GINA),[6] and the British Thoracic Society/Scottish Intercollegiate Guidelines Network.[9] 1 = suggested role ofomalizumab per the GINA guidelines.[6] More specific criteria for use of this product can be found in table IV. ICS = inhaled corticosteroid; PRN = asneeded.

Because of the difficulties inherent in avoiding asthma triggers, step 3 should be considered for patients with very poorly con-trolled symptoms at baseline (table I). Alternatives to these recom-drug therapy plays an important role in asthma symptom control.mended interventions include the addition of theophylline or aWhen prescribing and monitoring such pharmacotherapy, the gen-leukotriene modifier. Based on the omalizumab published exper-eral management and progression of treatment involves a step-iences[34,35,72-76] described in section 3, omalizumab may be addedwise approach with the intensity of treatment being ‘stepped up’to step 4/5 therapy in eligible allergic asthma patients who arefrom initial intermittent rescue treatment to the eventual use of onesymptomatic despite such therapy (see section 6.2).or more long-term maintenance therapies for patients whose

symptoms are poorly or only partially controlled at a given level of3. Omalizumab Clinical Outcomestreatment (table I and figure 2).[6,9] Assessment of response is

performed at regular intervals (typically every 3–6 months) to Omalizumab has been evaluated in four randomized, double-determine if treatment intensification or reduction must be consid- blind, placebo-controlled, clinical trials involving adolescents andered. adults with allergic asthma.[34,35,72,73] Each of these trials assessed

the benefit of adding omalizumab to existing asthma pharma-Patients with intermittent occasional daytime symptoms ofcotherapy (i.e. omalizumab was evaluated as ‘add-on’ therapy).short duration (step 1) may achieve symptom control with an as-Although the inclusion criteria for these trials targeted patientsneeded, short-acting inhaled β-adrenoceptor agonist. These agentswhose FEV1 values fell within the moderate-to-severe persistentrapidly reverse bronchoconstriction and its associated symptomsdisease severity categories, application of GINA staging guide-but are not intended for long-term disease maintenance.[6,9] Theylines reveal that most patients had severe persistent disease, basedare considered ‘rescue medications’ and should be prescribed toon the fact that symptoms were poorly controlled despite treatmentall asthmatic patients. Their increased use may signal a need forwith medium to high doses of ICSs.[6,77] Omalizumab utility hasintensifying drug therapy with regular maintenance medications asalso been assessed in a ‘real-life’ clinical practice setting, in adescribed in the remaining steps of the guidelines. For patientsmulticenter, open-label study. Adult and adolescent patients withwhose symptoms are more frequent, the use of long-term mainte-poorly controlled moderate to severe persistent allergic asthmanance medications is critical for minimizing symptom frequencywere randomized to receive best standard care plus omalizumab orand disease exacerbations. Inhaled corticosteroids serve as thebest standard care only.[74] Although a detailed discussion of thesebackbone of maintenance treatment (step 2). In general, as mainte-studies is beyond the scope of this publication, a summary of thesenance therapy requires intensification because of inadequate con-results can be viewed in table II.trol (steps 3–5), additional therapies can be added (the preferred

add-on agent is a long-acting inhaled β-adrenoceptor agonist) and/3.1 Safety and Tolerability

or the dose of inhaled corticosteroid (ICS) may be increased (theinitial low dose may be increased to a moderate dose and subse- Although one group of investigators reported a greater frequen-quently increased to a high dose). Although most treatment-naive cy of headache (17.5% vs 5.7%), cough (7.8% vs 1.9%), andpatients with persistent symptoms are initiated on step 2 treatment, nausea (6.8% vs 0.9%) with omalizumab therapy,[74] in random-



ized trials of adolescent and adult patients with allergic asthma, to previous injections of this product) and provide medicationguides for patients.[80]there was typically little difference between omalizumab and

placebo recipients with regard to adverse event reporting.[34,35,72-76] The product package insert for omalizumab also includes aLocal injection site reactions were associated with 8.6–20.4% of warning of malignant neoplasms.[78] Since the majority of patients

in clinical trials have had no more than a year’s exposure toomalizumab injections and 6.5–10.3% of placebo injec-omalizumab, the risk for malignancy with more prolonged treat-tions.[34,35,72,75] Soler et al.[34] found that bruising was the mostment needs to be studied, particularly in individuals who may be atcommon reaction reported by both omalizumab and placebo recip-higher risk for malignanciesients; redness, warmth and itching were more common among

omalizumab recipients. In studies that included descriptions of4. Omalizumab Humanistic Outcomes:laboratory monitoring with omalizumab treatment, no clinicallyAsthma-Related QOL and Perceptions ofsignificant changes in such values were observed.[35,73,74,76]

Treatment EfficacyUrticaria has been described in patients involved in someclinical trials;[34,35,72] however, it was not described as a common In omalizumab clinical trials, investigators included measuresadverse event. These reactions were typically mild or moderate in of HR-QOL and treatment efficacy perceptions.[72,73,81,82] In theseseverity, and usually resolved spontaneously despite continued trials, HR-QOL was evaluated via the AQLQ,[71] and impressionstherapy or resolved quickly with therapy discontinuation. The of therapy effectiveness were evaluated by asking patients to rateincidence of urticaria was similar among omalizumab and placebo treatment efficacy as excellent, good, moderate, poor, or worse. Inrecipients.[34,35,72] According to the initial product labeling, ana- the AQLQ assessments, a greater percentage of patients exper-phylaxis was reported in three patients (incidence of <0.1%).[78]

ienced a minimal clinically significant change in overall AQLQThese reactions occurred within 2 hours of a first or subsequent scores in three of the four omalizumab trials.[72,73,82] However, aomalizumab doses. Symptoms included urticaria and throat and/or significantly greater proportion of omalizumab recipients did ex-tongue edema. Respiratory failure was not observed, and all pa- perience a large improvement (quantitatively greater than a mini-tients survived. Based on recent reports of serious and life-threat- mal clinically relevant change) with omalizumab therapy in allening early (within 2 hours) and delayed (≥24 hours after injec- four trials. Meta-analyses involving several of the omalizumabtion) anaphylactic reactions, the US FDA, has requested that the trials reveal that a larger proportion of omalizumab recipientsmanufacturer add a boxed warning to the product label.[79] The experienced minimal, moderate, and large improvements in over-FDA also advised healthcare professionals to observe patients for all AQLQ scores.[83,84] Patients’ impressions of therapy effective-at least 2 hours after injection (even for patients without reactions ness were consistent with AQLQ evaluations, lending validity to

Table II. Summary of statistically significant clinical outcomes with omalizumab treatment of allergic asthma

Outcome parameter Soler et al.[34]a Busse et al.[35]a Holgate et al.[72]a Humbert et al.[73]a Ayres et al.[74]b

Exacerbation rate ↓c ↓c ↔ ↓ ↓

No. of patients with an exacerbation ↓c ↓c NA NA ↓

Exacerbation duration NA ↓ NA NA NA

ICS dose requirements ↓c ↓c ↓ NA ↓

No. of patients with discontinuation of NA ↓c ↔ NA NAICS therapy

Asthma symptom scores ↓ ↓ ↓ ↓ ↓

Nocturnal asthma symptom scores ↓ NA NA NA NA

Rescue medication requirements ↓ ↓ ↓ ↔ ↓

Morning PEF rates ↑ NA ↔ ↑ NA

FEV1 ↑ ↑ ↔/↑ ↑ ↑

a Comparison group was placebo.

b Comparison group was best standard care as outlined in an Expert Panel Report.[7]

c Significant differences were also noted during 24-week double-blinded extensions of the 28-week core studies.[75,76]

FEV1 = 1-second forced expiratory volumes; ICS = inhaled corticosteroid; NA = not assessed or p-values not reported; PEF = peak expiratory flow;↑ indicates an increase; ↔ indicates no change; ↓ indicates a decrease.



this simple assessment method. With assessments performed at the some patients. A plan’s deductible, percentage coinsurance, andend of the core trials, HR-QOL ratings were more likely to be good annual payment limit may make omalizumab therapy unafford-or excellent for omalizumab recipients; the percentage of patients able.indicating a good or excellent response was consistently and 2. Whether the specialty pharmacy is in the health plan/payer’ssignificantly greater among omalizumab recipients in the three network (if not, the SMN is faxed to one of the other four specialtytrials in which this was assessed.[73,81,82] Approximately 61–70% pharmacies within the health plan/payer’s network).of omalizumab recipients rated their response in this manner 3. Prior authorization requirements. The specialty pharmacy(compared with approximately 38–43% of placebo recipients, sends the SMN to the patient’s health plan/payer to obtain approv-p < 0.001 in each trial).[35,73,81,82] Similar differences were reported al to dispense omalizumab for eligible patients.with investigator evaluations of patient clinical response. While health plans/payers may limit the use of omalizumab to

patients who meet the FDA-approved indication, other health5. Omalizumab Economic Considerations plans/payers may place additional restrictions that are more strin-

gent. For example, Blue Shield of California uses the followingspecific prior authorization criteria: prescription by an allergist or5.1 Drug Acquisition Process and Coverage/pulmonologist; documented history of persistence for >1 year;Reimbursement in the USprior use of standard therapies (omalizumab should not be used asfirst-line therapy); inadequate response during the past year (asOmalizumab was approved by the FDA in June 2003 and isevidenced by an asthma-related emergency room visit, inpatientcurrently approved for use in 52 other countries, including Cana-admission, or unscheduled outpatient visit); a high IgE level;da, the EU, Australia, and Brazil.[85] However, as of January 2007,documented prior use of the maximum tolerated ICS; restriction tothe Scottish Medicines Consortium has not recommended its usenon-smokers. This plan’s approval is for 6 months, with subse-for people with severe asthma.[86]

quent extension if the patient has complied with the therapyOmalizumab must be obtained through a non-standard approvalregimen and shows evidence of improvement.[88] Other plans/and distribution process that can be time and labor intensive, apayers may require documentation of levels of FEV1 abnormality,factor that may need to be considered when the total cost ofsystemic corticosteroid use, doses of current asthma medications,therapy is being evaluated. To begin the process of obtainingfailed therapies, the patient’s physical limitations and asthma-omalizumab, two forms must be completed: (i) the Patient Author-related symptoms, and/or a certificate of medical necessity.[87,89,90]ization Notice of Release of Information (PAN); and (ii) the

Although healthcare providers can obtain payer approval them-Statement of Medical Necessity (SMN). The SMN form requestsselves, the drug would still need to be obtained through one of theinformation that may be needed by the health plan/payer reviewerspecialty pharmacies. Under this circumstance, the provider wouldto assess medical necessity and authorize its use: health insuranceneed to forward prior authorization documentation to the specialtycoverage, prescriber name and specialty, diagnosis and medicalpharmacy. After omalizumab has been administered, the providerinformation (patient weight, ICD-9 diagnosis codes, concomitantfiles a claim to the patient’s health plan/payer for reimbursementasthma therapies, documentation of a positive skin or radioal-of the cost of omalizumab and associated administration costs (i.e.lergosorbent test [RAST] to a perennial aeroallergen, a pre-treat-physician compensation for professional services related to thement IgE serum level, medical justification for prescribing omal-administration of omalizumab).izumab), and prescription information (dose, number of refills).

The drug and the accompanying ancillary materials (diluent,The two forms are faxed to a specialty pharmacy chosen by the3cc syringe and 18-gauge needle for reconstitution, 25-gaugeprescriber.needle for administration, alcohol swabs) may be shipped to theThe manufacturers have contracted with five specialty pharma-provider or directly to the patient. However, clinicians are advisedcies that serve as the primary distribution network for omalizumabto have these materials delivered to their office practice becausein the US. These pharmacies also provide assistance with theomalizumab must be shipped at ≤30ºC and stored refrigerated atreimbursement process and patient education services. When a2–8ºC prior to reconstitution.[78]specialty pharmacy receives the PAN and SMN, it investigates

three matters regarding the initial referral:1. A patient’s health insurance benefits (to determine whether the 5.2 Drug Product Cost and Administration Issuespatient’s plan covers omalizumab). Although most private andpublic plans provide coverage for appropriate omalizumab candi- According to prescribing information, omalizumab is adminis-dates,[87] cost-sharing obligations may still present a challenge for tered only by subcutaneous injection in standardized doses intend-



ed to provide an approximate dosage of at least 0.016 mg/kg per Bodyweight (kg) × pretreatment IgE (IU/mL) × 0.016 = dose/28 daysIU of IgE/mL per 4 weeks.[78] Dosages of 150mg or 300mg are

By utilizing this administration formula, Rambasek andadministered every 4 weeks. Larger dosages (450mg, 600mg, orKavuru[92] calculated that the average cost per patient could be750mg every 4 weeks) are divided and administered every 2reduced by as much as 32%. These authors also point out that drugweeks. As shown in table III, the lowest dosage regimen (150mgwaste (unused drug is discarded) might be minimized by consider-every 4 weeks) will cost $US7721 per year, while the largesting a deviation from the standard 2- or 4-week administrationdosage regimen (375mg, or three vials, every 2 weeks) will costinterval schedule (i.e. administering 150mg [contents of one vial]$US46 323 per year for the drug alone.[91] In practice, the actualevery 24 days for the patient whose formula-derived dosage isacquisition cost of the drug may be lower than the average whole-173mg [contents of two vials] every 28 days would provide thesale price because of contractual discounts and rebates. Dosagesame degree of drug exposure). As cautioned by Rambasek andrequirements for the majority of patients will likely be >150mgKavuru,[92] more research is required to elucidate the most appro-

every 4 weeks, as the 150mg regimen is used only for patients whopriate method for determining omalizumab dose regimens.

are ≤90kg AND have serum IgE levels at the lowest end of theWhen scheduling appointments for omalizumab administra-

range (30–100 IU/mL). In the omalizumab clinical trials, the meantion, additional planning is required on the part of the provider.

serum IgE concentrations were between 167 IU/mL and 267 IU/The single-use product vials must be administered within 4–8

mL.[34,35,72-74] Therefore, an average omalizumab dosage may be hours of reconstitution (they are preservative free), and the drug300mg every 4 weeks or 225mg every 2 weeks depending on the takes 15–20 minutes to dissolve. To avoid unnecessary waste, thepatient’s bodyweight. As the dosage and administration schedule trigger for initiating the drug preparation process is likely to be theof omalizumab are based on the patient’s weight and baseline patient’s arrival. Additionally, as discussed in section 3.1, it isserum IgE levels,[78] measuring a serum total IgE level (IU/mL) recommended that the patient stay at least 2 hours after thebefore the start of treatment adds to the total costs of therapy. injection and be observed for possible severe hypersensitivity

reactions.Although the standardized administration recommendationsAlthough providers may wish to coordinate injections for mul-found in the omalizumab prescribing information simplify dose

tiple patients to avoid drug waste, there is currently no literaturedeterminations, Rambasek and Kavuru[92] have reported that ad-describing such an effort. Additionally, this practice may be ham-ministration in this fashion may result in the administration ofpered by the intricate acquisition process, short time windowhigher than necessary doses, particularly in patients whose serumbetween reconstitution and injection, and the fact that providersIgE level and weight are both at the lower end of the cutoff valuesmay not have a sufficient volume of patients receiving this prod-in the administration tables. Since the table has been developed touct.ensure that each patient receives a dosage of omalizumab of at

least 0.016mg/kg bodyweight/IU/mL of free IgE per 4 weeks, a5.3 Resource Utilization anddose may be calculated using the following formula:Pharmacoeconomic Analyses

From the outset of the 2003 FDA approval of omalizumab,there have been concerns regarding the cost effectiveness of thisproduct because of its high acquisition cost.[12-16,93] An economicanalysis has shown that it may not be cost effective to administeromalizumab to patients who do not consume large amounts ofasthma resources.[94] Oba and Salzman,[94] utilizing a third-partypayer’s perspective, performed a retrospective economic analysisof direct costs to evaluate the cost effectiveness of omalizumabusing data from two of the previously discussed clinical trials.[34,35]

Using cost estimates for 2003 and a wholesale omalizumab acqui-sition cost of $US433 per 150mg vial, the authors estimated thatthe average daily treatment cost for omalizumab recipients was$US39.85 per patient compared with $US2.08 per patient forplacebo recipients. The significant difference between the two

Table III. Annual drug cost for omalizumab

Dosage regimen Vials/injections Drug costper dosea ($US)b

150mg every 4 weeks 1 7 721





a 150mg dose is delivered in a 1.2mL volume. Because of theviscosity of the product, each injection should be no more than1.2 mL. Doses >150mg need to be administered with separateinjections. Omalizumab for subcutaneous administration is for singleuse only; any remaining unused product is discarded.

b Based on average 2006 wholesale price of $US593.89 per 150mg ina 1.2mL vial.[91]



treatments was primarily due to drug product cost. The average rhinitis,[99] and one is unpublished at the time this review wasdaily cost associated with utilization of other healthcare resources written). As was observed in the original publications, omal-was $US0.08 and $US0.36 per patient for the omalizumab and izumab recipients had lower asthma exacerbation rates. Addition-placebo recipients, respectively. The cost of gaining one additional ally, omalizumab recipients had 52% lower rates of hospitalizationsuccessfully controlled day with the use of omalizumab was (p = 0.041), 61% lower rates of emergency room visits (p = 0.013),$US523. Oba and Salzman,[94] suggest that omalizumab could and 43% lower rates of unscheduled doctor visits (p < 0.001)result in cost savings only if administered in a patient who is compared with control. Based on the results of the analysis,hospitalized at least five times or 20 days per year, or requires at approximately five patients would have to be treated for 1 year toleast seven monthly emergency room visits for treatment of asth- avoid one unscheduled doctor visit, 25 would have to be treated forma-related events. Hence, these and other authors recommend its 1 year to avoid one emergency room visit, and 31 would have to beuse be restricted for suboptimally controlled moderate to severe treated for 1 year to avoid one hospital admission.allergic asthma in patients requiring regular use of intensive With the data from three randomized trials in adults and adoles-healthcare resources for management of exacerbations.[11,14,15,95,96] cents with allergic asthma,[34,35,72] Holgate et al.[100] performed a

meta-analysis to evaluate the impact of omalizumab on an annual-Although others have questioned the validity of the outcomeized rate of all asthma exacerbation episodes (AEEs) and signifi-measures utilized by Oba and Salzman,[94] even such critics agreecant AEEs (sAEEs; an exacerbation requiring doubling of the ICSthat the costs of omalizumab use are prohibitive in most pa-dose or use of systemic corticosteroids) among patients who weretients.[13] Utilizing the same data available to Oba and Salzman,[94]

at high risk of serious asthma-related morbidity and mortalityMiller and Reeves[13] calculated incremental cost-effectiveness(defined as those patients who had ever been intubated or who,ratios (ICERs) between omalizumab and placebo administration,within the year prior to enrollment, had visited an emergencyresulting in $US88 837 to prevent one unscheduled office visit,room, required an overnight hospitalization, or needed intensive$US577 812 to prevent one hospitalization, and $US755 600 tocare unit admission for an asthma exacerbation). Consistent withprevent one emergency department visit per year. In anotherthe initial reports of all enrolled patients, the rate of AEEs andeconomic analysis, a group of investigators used the results fromsAEEs was lower with omalizumab treatment than with placebo.one of the omalizumab clinical trials[73] to model the outcome andThese differences translated into the need to treat five patients withtreatment costs over the expected lifetime of severe asthmaticomalizumab to maintain one patient free of an sAEE, and fourpatients in Sweden.[97] Compared with standard therapy, omal-patients to maintain one patient free of any exacerbation for theizumab recipients would gain an additional 0.76 quality-adjustedperiod of study (average of 41.7 weeks for the three studies). In anlife-year (QALY) at an additional cost of €42 754, producing ananalysis by Humbert et al.,[73] it was found that approximately twoICER of €56 091/QALY. Approximately 85% of the QALY gainpatients needed to be treated with omalizumab for 1 year towas from a prolongation of life; 15% was the result of a betterprevent one clinically significant exacerbation.quality life. This ICER is comparable to the ratios reported for

other expensive biologicals (e.g. etanercept and infliximab) and is6. Managed Care Implicationsslightly above the cost-effectiveness threshold for Sweden.[97] In a

pharmacoeconomic analysis of a subgroup of patients (those re-ceiving high-dose ICSs and a long-acting inhaled β-adrenoceptor

6.1 Considerations for Managed Care Organizationsagonist) included in the ‘real-life’ clinical practice study[74] men-tioned in section 3, an ICER of €31 209/QALY (95% CI 27 739, Because omalizumab could have a major impact on a health40 840) was reported; this finding was considered to have a 69.7% plan’s asthma- and allergy-related direct medical costs (drug costsprobability of being cost effective in this population.[98] in particular), health plans/payers may need to employ strategies

Investigators have utilized data from clinical trials to better commonly used to manage the use and cost of drugs, especiallyquantify the impact of omalizumab on the clinical outcome and high-cost biologics.[88] These groups will have to evaluate how andhealthcare resource use in populations of patients documented or where omalizumab fits in drug formularies and policies regardinganticipated to have high asthma resource utilization.[42,50] Bous- restricted access. Because of product cost, omalizumab will likelyquet et al.[77] pooled the data of patients with severe persistent be placed in a ‘restricted use’ category, where prior authorizationasthma from seven adult-adolescent trials of allergic asth- is needed to dispense omalizumab to patients who meet specificma[34,35,72-74,99] (five of which are mentioned previously in section criteria (see table IV for proposed criteria). This process is likely to3,[34,35,72-74] one is not discussed in this review because it enrolled also require periodic re-evaluation (i.e. recertification) of continu-patients with concomitant allergic asthma and perennial allergic ing medical needs based on the patient’s condition and response to



Table IV. Proposed criteria for omalizumab use (reproduced from Belliveau and Lahoz,[15] with permission)

Criteria Comment

Patients should fulfill all of the following:

High-riska patient with severe persistent asthmab US FDA-labeled indication is for moderate-to-severe asthma, but product costmay dictate stricter criteria[34,35,72-78,94,97,98,101]

Age >12 years FDA-labeled indication[78]

Symptomatic despite 3- to 6-month trial with appropriate asthma Appropriate maximal maintenance therapy for severe persistent asthma:therapy high-dose ICS (>800 μg/day BDP, CFC or equivalent) plus LABA ± oral

corticosteroid[6,7,27,78,101] c,d

Allergic triggers and environmental controls have been addressed Evaluation by an allergy/immunology specialist might be considered toaddress these issues[6,7,27]

Patient inhaler technique, education, and adherence has been Guidelines consider patient education and compliance key components ofmaximizede establishing disease control[6,7,37]

Serum IgE 30–700 IU/mL Required to help establish that the patient has allergic asthma. Administrationper the product labeling does not give guidance for IgE concentrations outsideof this range[78]

Bodyweight 30–150kg Administration per the product labeling does not give guidance for patientweights outside of this range[78]

Positive skin-prick testing or RAST for perennial aeroallergen Per the product labeling. Required to help establish that the patient hasallergic asthma[78]

a High-risk patients include those with a recent history (within the prior year) of frequent intubations, emergency room visits, overnighthospitalizations, or intensive care unit admissions for asthma exacerbations.

b The severity of asthma may be classified by the frequency of symptoms and pulmonary function assessments prior to starting asthma therapy.However, since the criteria presented here apply to treatment-experienced patients, patients may be considered to have severe persistent diseaseif they require therapy consistent with this degree of disease despite not fulfilling the symptom frequency or pulmonary function requirements forsevere persistent asthma. A low FEV1 (particularly ≤65%) is more predictive of response than higher FEV1 values at treatment initiation.

c If a patient requires long-term corticosteroid maintenance therapy for symptom management (i.e. corticosteroid-dependent asthma), omalizumabmay be considered to reduce the exposure and long-term risks of this therapy even if such therapy provides adequate control.

d A health plan/payer may also consider trials of other add-on therapies (theophylline or a leukotriene modifier) as a criteria for use.

e If adherence and/or inhaler technique cannot be maintained despite documented adequate training and education, omalizumab may be consideredif all other criteria are fulfilled.

BDP = beclomethasone dipropionate, CFC = chlorofluorocarbon-containing; FEV1 = forced peak expiratory flow volume in 1 second; ICS = inhaledcorticosteroid; LABA = long-acting β-adrenoceptor agonist; RAST = radioallergosorbent test.

treatment. As a condition for reimbursement, health plans/payers average, 20–30% more expensive than those reimbursed throughare also likely to require that documentation of inadequate patient the pharmacy benefit.[103] For omalizumab, SMN coding require-response to appropriate step therapy be included on the omal- ments and specifications enable health plans/payers to distinguishizumab SMN before ‘stepping-up’ to omalizumab (as described in between the cost of the drug and professional fees.[88]

the example of Blue Shield of California in section 5.1). Patient cost-sharing provisions for medical benefits and phar-Additional issues that health plans/payers need to consider macy benefits vary greatly between plans.[87,88] In some medical

include the following: is omalizumab to be considered a pharmacy benefit plans, a patient may be required to pay for the physicianor a medical benefit?[88,102] Pharmacy benefits cover oral drugs office visit copayment, 100% of the product cost up to a drugobtained by patients from a pharmacy, while medical benefits deductible (e.g. $US250), and 20% of the product cost beyond thecover physician services and the products administered by physi- drug deductible.[88] A pharmacy benefit plan may require a patientcians in their offices.[88] Office-administered drugs, such as omal- to share the cost of omalizumab therapy either as a percentageizumab, historically have been covered under the medical bene- coinsurance or a dollar copayment. Health plans/payers that coverfit.[88,102,103] However, health plans/payers may be charged premi- high-cost specialty drugs under their pharmacy plan are increas-um prices for office-administered specialty drugs,[102] since such ingly using this percentage coinsurance option to increase the costproducts reimbursed through the major medical benefit are, on sharing for such products.[103]



Although clinical trials have shown omalizumab to have a ICS- ratio for response with all three factors present was 4.20; 95% CIsparing effect, the clinical and cost significance of this benefit is 1.69, 10.45). Baseline IgE concentrations were not predictive ofstill questioned.[104] However, with appropriate screening for pa- response. Among patients showing a response to omalizumab attients who are most likely to benefit, the use of this product could 16 weeks, 61% had responded by 4 weeks, and 87% had respond-result in a reduction in the cost of care for patients who utilize ed by 12 weeks of therapy. In another analysis of data pooled fromlarge amounts of resources. To address this issue, a health plan/ seven trials in adult and adolescent patients with allergic asthma,payer might review the disease demographics of its enrollees. In the efficacy (in terms of relative rates of asthma exacerbations) ofparticular, a health plan/payer would need to know the number of omalizumab in patients with severe persistent asthma was notpatients with asthma that it serves, and determine the distribution changed by patient age (for those aged <65 years), sex, baselineof disease severity of these enrollees. Additionally, it could review IgE, or by the administration schedule utilized (administrationthe amounts spent on the most severe, highest cost patients with

every 2 or 4 weeks according to the recommendations).[77] Effica-allergic asthma who may have incurred expenses because of

cy was better for omalizumab recipients across all baseline severi-poorly controlled disease. Expenditures for these patients would

ties (as measured by FEV1). However, there appeared to be a trendthen be compared with what it would cost to pay for omalizumab

for greater relative improvement in patients with the worst lungin such patients. The plan/payer could determine if the anticipatedfunction.reduction in resource utilization (e.g. fewer hospital admissions,

reductions in emergency department use and outpatient visits, and/6.2.2 Selection Criteria for Omalizumab Prescribingor less ICS use) with omalizumab administration in these patientsAs suggested in the newest GINA asthma treatment guidelines,would sufficiently offset the costs associated with product acquisi-

omalizumab might be considered for add-on therapy in a patienttion, preparation, and administration. Plans/payers may also wishwith allergic asthma not responding to preferred step 4 or 5to include an assessment of omalizumab therapy on treated pa-

tients’ QOL. therapies (figure 2). However, despite the FDA-labeled indicationthat includes symptomatic adults/adolescents with moderate toAfter omalizumab has been placed on the formulary, a health

plan/payer may want to analyze the resource utilization of patients severe persistent allergic asthma, the product cost and databefore and during omalizumab therapy. A health plan/payer may presented within this article may dictate narrowing criteria furtheralso wish to examine the effectiveness of its criteria of medical to only include symptomatic ‘high-risk’ patients with severe per-necessity and closely monitor whether prescribers and/or prior sistent allergic asthma (see table IV). This defines a populationauthorization reviewers are adhering to these criteria. that is consistent with the group of patients having severe/refracto-

A health plan/payer may also track denial rates, and the poten- ry asthma according to an American Thoracic Society Workshoptial impact of such denials (i.e. compare the direct medical costs of consensus definition.[105]

patients who received omalizumab with those who were denied itsAs most patients appear to respond within the first 3 months of

use).[93]

omalizumab therapy, clinical re-evaluation should be performedwithin this timeframe and therapy discontinuation should be con-

6.2 Proposed Criteria for Omalizumab Use sidered in the absence of a response. Table IV highlights these andother parameters that managed care organizations should consideras part of their criteria for the use of omalizumab. As would be6.2.1 Predicting Responseexpected, some of the required information, such as the serum IgETo date, few investigations in patients with allergic asthmalevel and skin-prick/RAST testing, are used to establish that thehave provided insight into factors that correlate with a response topatient’s symptoms are allergic in nature. However, it should beomalizumab. Bousquet et al.[101] pooled data from two of thenoted that the allergic asthma trials have enrolled patients withrandomized clinical trials in adults and adolescents with allergicsensitivity to perennial aeroallergens. Although there are dataasthma[34,35] to identify the baseline patient characteristics that aresupporting the use of omalizumab in the treatment of patientspredictive of response to omalizumab. Logistic regression analysispresenting with concomitant perennial allergic rhinitis[99] and al-of the data from the first 16 weeks of these trials revealed that thelergic asthma, or in patients with just seasonal allergic rhini-following characteristics were predictive of response: a history oftis,[106-108] there are no studies to date evaluating omalizumab inemergency asthma treatment in the prior year, a baseline require-patients whose allergic asthma episodes correlate primarily withment for high dosages (≥800 μg/day) of inhaled beclomethasoneexposure to seasonal allergens.dipropionate, and a baseline FEV1 of ≤65% of predicted (the odds



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Practice and Assistant Dean of Pharmacy at the Massachusetts College of17

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TrendsRx® Quarterly 2003; (1): 4-5 [online]. Available from URL: http://Worcester/Manchester, 1260 Elm Street, Manchester, NH 03101-1305, USA.www.caremark.com/portal/asset/TrendsRxQuarterlyNewsletter_8-15.pdf [Ac-E-mail: [email protected] 2007 Mar 28]


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