The introduction of human immunoglobulin (Ig) therapies 40 years ago reduced the risk of often life-threatening infections for individuals with one of several immune-related conditions known as primary immunodeficiencies. Since then, the use of Ig has expanded to numerous other conditions. However, even though less than 1% of covered lives under Medicare or commercial insurers require Ig, it is in the top 5 drug categories in terms of annual spending. The cost of Ig is directly related to the type of delivery method used and the site of care. Numerous studies attest to the efficacy and cost savings of shifting Ig to the home setting, as well as shifting patients from intravenous Ig (IVIG) to subcutaneous Ig (SCIG). In addition, surveys find that patients with primary immunodeficiencies prefer home delivery, with patient evaluations also finding a preference for SCIG. Payers have numerous options to ensure Ig is used appropriately for the right patient in the right setting. These include formulary management, site-of-care programs, education for providers and patients on the possibility of switching from IVIG to SCIG, preauthorization policies that restrict the use of Ig to certain specialties for specific indications, implementation of evidence-based coverage criteria, and shifting coverage from the medical to the pharmacy benefit.
Am J Manag Care. 2019;25:-S0
Primary immunodeficiencies are a heterogenous group of immune-related conditions in which individuals exposed to pathogens risk severe and often life-threatening infections. The first patient with primary immunodeficiency was treated with subcutaneous human immunoglobulin (Ig) in 1952, transforming the outlook for these patients.1 The use of Ig has since been shown to reduce the risk of infection, antibiotic use, and hospital admissions, while leading to improved growth in pediatric populations and the maintenance of normal pulmonary function, thus dramatically improving quality of life and prognosis.2,3
Today, Ig is also used on- and off-label for the chronic and acute treatment of numerous other conditions, including chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN); to prevent bacterial infections in patients with certain hematologic malignancies, pediatric HIV, chronic lymphocytic leukemia, or following bone marrow transplantation; to increase platelet count in patients with idiopathic thrombocytopenic purpura; for certain autoimmune diseases, such as myasthenia gravis, immune-mediated inflammatory myopathies, immune-mediated blistering diseases, stiff person syndrome, and others; and to treat immunologic deficiencies in patients receiving B-cell—depleting targeted therapies.4,5 Ig is primarily used in its intravenous (IVIG) and subcutaneous (SCIG) formulations. Both can be delivered via an infusion pump; this often provides greater ease and convenience for patients and their families.4
Igs are one of the most complex specialty drugs for payers to manage. There are several reasons for this, including the large number of products currently on the market, which all have various doses, formulations, and indications; off-label uses; and adverse effects (AEs). Other important factors include patient and family education, the administrative support required, and site-of-care issues related to product delivery.6,7
The use of Ig is also increasing as diagnoses of primary immunodeficiencies and neurologic conditions increase, the population ages, and new uses are identified.8,9 For instance, the number of Medicare beneficiaries with primary immunodeficiencies receiving IVIG grew 60% between 2010 and 2014, with 25% of patients being younger than 65 years.10 In 2016, the Jeffrey Modell Foundation reported a 19% global increase in the number of patients receiving Ig between 2013 and 2015, with a 7% increase in those receiving IVIG and a 100% increase in those receiving SCIG. In the United States, the number of people with primary immunodeficiencies receiving Ig increased 11.5% during that time, with a 10% increase in IVIG administration and a 39.3% increase in SCIG administration.11 However, primary immunodeficiencies still remain undiagnosed, underdiagnosed, or misdiagnosed. Not only does this increase the risk of mortality for patients, but it also results in higher costs for payers.11,12
Economic Burden of Chronic Immunodeficiency Diseases
A 2017 report from the Jeffrey Modell Foundation that used the IMS database containing medical and pharmaceutical claims for more than 60 million patients from 90 US health plans found that annual treatment costs for patients with primary immunodeficiencies declined from $111,053 per patient before diagnosis to $25,271 per patient after diagnosis, even before Ig treatment.13 Even accounting for an annual $30,000 per patient cost of Ig, total cost savings post diagnosis were $55,882 (Table 113).
A retrospective analysis of a large commercial database identified 1388 patients undiagnosed with primary immunodeficiencies for at least 5 years (84 for at least 10 years). Patients had a mean 39% increase in pneumonia, 20.4% in sinusitis, 20.2% in bronchitis, and 14.2% in otitis in the 10 years before diagnosis. In addition, there was a 29.1% average annual increase in hospitalizations, 10.5% in outpatient visits, and 5.3% in outpatient drug utilization.14
Other studies highlight the costs of other conditions for which Ig is used. One analysis of 31,451 medical records estimated the cost of hospitalizations for CIDP between 2010 and 2012 at $2.1 billion. Each CIDP hospitalization cost an average of $68,231, which was higher than that of a matched cohort, although the authors did not specify the cost of hospitalization for controls. The patients with CIDP also had lengths of stay 50% longer than controls.15
Cost of Immunoglobulin
In 2016, commercial payers spent an average of $2.00 per member per month (PMPM) on Ig (average claim $4154), a 16% increase over the previous year. The category represented the third highest drug category for payers at 8% of total drug spending, even though fewer than 1% of members (0.41 per 1000) required Ig treatment.16
Ig represents the fourth highest drug spending for Medicare Advantage plans, with an average PMPM of $2.82 in 2016 and an average cost per claim of $3282, representing 6% of overall Medicare Advantage prescription drug spending that year. The number of Medicare Advantage beneficiaries utilizing Ig, although higher than the commercial population, is still less than 1% (0.97, per 1000).16
Site of Care
When it was first approved, IVIG was typically delivered in the hospital setting as that was considered a safer place to manage AEs. Today, however, IVIG and SCIG may also be delivered in the home or physician office setting.17 The Jeffrey Modell Foundation estimated that 38% of US patients with primary immunodeficiencies received IVIG in a clinic setting in 2015 and 30% received IVIG in the home setting, whereas 28% of patients received SCIG (Table 2).11 Since then, many payers have instituted site-of-care policies, so these percentages are likely higher.18,19 Guidelines from the American Academy of Allergy, Asthma and Immunology note that the decision as to where to infuse the drug should be based on clinical considerations, including patient experience, patient comorbid conditions, and circumstance.20
In 2015, 48% of IVIG covered by commercial payers was delivered in the home or specialty pharmacy setting, 30% in the hospital outpatient setting, and 24% in the physician office setting, which represents a slight decline in hospital setting delivery from 2014 (33% to 30%). Under Medicare Advantage, 36% was delivered in the home or specialty pharmacy setting, 38% in physician offices, and 26% in hospital outpatient settings. This represents a significantly higher decline in hospital outpatient delivery between 2014 and 2015 (35% to 26%) in the managed care Medicare environment.21
The outpatient hospital setting can be the most expensive site for delivery of IVIG for commercial payers (Figure 1).17 This is because reimbursement is typically based on a percentage of billed charges plus a facility fee. Reimbursement in physician offices and nonhospital-owned clinics, however, is based on the cost of the drug plus an administrative fee, whereas home infusions are typically paid at average wholesale price minus any discounts or average sales price plus a percentage, plus equipment and nursing reimbursement.22 It is important to keep in mind that there are multiple reimbursement scenarios in each site of care (hospital, hospital outpatient, physician office, home), which vary based on the payer and the route of administration.
SCIG products may be more expensive than IVIG agents when considered on a per-gram basis. Although this is important to factor in, there are various considerations to examine when analyzing cost-effectiveness. Several analyses discuss substantial savings when IVIG administration shifts to the home setting and/or when patients switch from IVIG to SCIG formulations. A French analysis of IVIG costs in 24 patients (9 with MMN, 8 with CIDP, and 7 with Lewis-Sumner syndrome) found 1-year costs of $54,914 for patients treated in the home versus $104,608 for those treated in the outpatient hospital setting (P <.0001). The authors estimated that 20% of current patients with CIDP could benefit from the switch, with the number as high as 80% among stable patients.23
Another retrospective review of a claim database covering nearly 43 million participants in a commercial health plan also found lower overall costs for home infusions, with the cost per infusion per patient to be 31% less in the home setting than in the outpatient setting ($3293 vs $4745; P <.0001) (Figure 1).17 Overall, the investigators estimated that delivering IVIG in the home setting could provide annual savings of $18,876 to $26,136 for each patient receiving 13 to 18 infusions per year. The analysis also found lower non-Ig costs (Table 317) and improved adherence in patients who received home infusions (47% vs 22%; P <.001) based on the recommended 13 to 18 infusions per year. A significantly greater number of patients with fewer than 7 infusions per year were in the outpatient hospital versus the home setting (39% vs 29%; P <.0001).17
Ye et al used a large commercial claims database to identify patients with at least 3 months of continuous IVIG and compared costs of care among the home, outpatient hospital, or clinic setting. Eighty-three patients switched their IVIG site between clinic and home, and 79 switched between outpatient hospital to home. Switching from the outpatient hospital setting to the home setting led to significantly lower median costs ($6916 vs $4188; P <.0001), although there were no significant differences in costs between the clinic and home setting.24
A study by Wasserman et al used data from a large, US-based commercial database to identify outcomes related to IVIG site of service. Of the 1076 patients with primary immunodeficiencies included in the analysis, 51% received IVIG at home and 49% at a hospital-outpatient infusion center. Patients receiving home-based infusions had significantly lower rates of pneumonia (0.102 vs 0.216; P = .0071) and bronchitis (0.150 vs 0.288; P <.0001) independent of prophylactic antibiotic treatment.25 The differences were significant in the first 3 weeks after the first infusion with no significant difference following the fourth infusion, suggesting, the authors noted, that the setting itself may be a factor in the infection rate. The findings are particularly significant given that recurrent lower respiratory infections eventually lead to the long-term pulmonary disease that is a major cause of morbidity and mortality in these patients.25
Given the lower cost of at-home or physician office administration, many payers have introduced sites-of-care policies related to infusions.18,26,27 This includes removing reimbursement incentives between sites of care; encouraging patients to choose less-expensive sites of care through education, communication, and financial incentives; and restricting settings based on medical necessity or specific patient issues.28
In a survey of 59 commercial health plans representing more than 76 million covered lives, there was a 135% increase in plans using site-of-care programs between 2013 and 2017 (26% to 61%). More than half of those without a site-of-care program in 2017 planned to implement one in the next 12 months. Of those with site-of-care programs, 89% have one for IVIG, making it the top therapeutic area with site-of-care programs.29
The majority of Medicare fee-for-service IVIG (and other infusions covered under Part B) are delivered in the hospital-owned outpatient setting, physician offices, or skilled nursing facilities, primarily because of financial issues.30 Traditional Medicare has not, until now, reimbursed supplies and administration for in-home IVIG outside a current pilot program, although it does provide a bundled payment for SCIG.10,31 A 2014 report from Avalere Health estimated Medicare could save $80 million in infusion services between 2015 and 2025, or 12.6% of overall infusion costs, by encouraging a shift to home infusion.30
In 2012, Congress established a 3-year Patient Intravenous Immunoglobulin Access Demonstration project, designed to enroll up to 4000 beneficiaries with primary immunodeficiencies. The demonstration required Medicare to provide a bundled payment to providers for items and services required to administer in-home IVIG, including services provided by a skilled nurse.10,31 It is important to note that the Demonstration project has been extended beyond the initial 3-year period and results have not yet been published.
IVIG versus SCIG
There is a movement to shift patients from IVIG to SCIG given numerous studies demonstrating clinical equivalence between the two with lower overall costs and improved patient satisfaction with SCIG administration. SCIG drugs may be more expensive per gram and that is important to take into consideration. When additional costs are factored in, including administration fees and site-of-care fees, several studies found lower overall costs.
Fu et al conducted a 12-month prospective observational study that analyzed overall costs for 30 patients receiving IVIG and 27 receiving SCIG. Patients on SCIG received training from a nurse during a single visit, then infused the product on their own at home; in contrast, those on IVIG therapy spent 2 to 3 hours in a hospital-based setting receiving the infusion.32 Total costs to the hospital and health-system costs in the SCIG group were $1836 and $1920, respectively, compared with $4187 and $4931, respectively, for the IVIG group (Figure 2).32 The lower costs were due to fewer physician and hospital visits and shorter total nursing time required for the infusion (Figure 2).32
Moreover, a German cost-minimization analysis on the effects of switching patients with primary immunodeficiencies from hospital-based IVIG to home-based SCIG over 3 years found that SCIG cost $35,438 per patient the first year and $30,441 in subsequent years compared with $34,638 per year for IVIG, resulting in a total savings of $7592 per patient over 3 years, even given additional costs for equipment and patient training.33 These are based on a CHF (Swiss currency) to USD conversion (of note, the USD used to have a stronger value than Swiss franc until April 2019; now the Swiss franc is stronger than the USD).
In addition, an analysis of direct medical and indirect costs in 25 pediatric patients who received either SCIG or IVIG in a pediatric clinic also found significantly lower medical costs in the SCIG cohort, as well as nonmedical costs, including travel expenses and parental time (P <.001 for both) (4706 vs 2131; P <.001). Although the study was conducted in Canada, the authors noted that it “could easily be applicable to most healthcare systems in the Western world.”34
In France, analysts used a cost-minimization analysis with a simulation model to compare hospital costs and transportation in the outpatient and home setting for IVIG and in the home setting for SCIG. Authors concluded that direct medical costs ranged from $22,211 for home-based IVIG to $29,164 for hospital-based IVIG, with home-based SCIG at $28,445. A patient satisfaction questionnaire demonstrated greater satisfaction in terms of convenience with SCIG as well as greater satisfaction with either home SCIG or IVIG versus hospital-based.35
Finally, Canadian researchers conducted a cost-minimization and budget-impact model to evaluate the economic benefits of replacing IVIG with rapid push SCIG in Canadian patients with primary immunodeficiencies over 3 years.36 Under the cost-minimization model, rapid push SCIG was $1487 vs $5800 (USD) for IVIG, reducing per-patient healthcare costs in Canada by 74% ($5765 for IVIG vs $1478 for SCIG) over 3 years, primarily as a result of fewer hospital staff required. The authors estimated that if half of eligible patients switched to SCIG, the cost savings for the healthcare system would be $977,586. If 75% of patients switched, that figure reached $1.47 million. The model applied 85% of the total cost to the Ig itself.37
There is good evidence that patients much prefer infusions in the home environment. One systematic review of the literature found that home infusion care provided safe, clinically effective care with improved quality of life and reduced overall healthcare costs.36,38 In addition, patient satisfaction with SCIG was demonstrated in a recent analysis from the Polyneuropathy and Treatment with Hizentra (PATH) study, which is the largest trial ever to compare relapse rates in patients with CIDP. Investigators randomized 172 IVIG treatment-dependent patients to weekly infusions of placebo or low- or high-dose SCIG. As expected, patients in the SCIG groups had significantly fewer rates of relapse than those in the placebo group. More importantly, the rates of relapse in the SCIG patients were similar to those experienced while on IVIG. Patients preferred the weekly SCIG treatment to monthly IVIG because of a gain in independence and fewer AEs. The results, the authors wrote, suggested that SCIG may be an alternative option as a maintenance therapy for patients with CIDP.39
Other Cost-Management Approaches
In addition to site-of-care policies, payers use a variety of other approaches to manage the cost and appropriate use of Ig, as shown in Table 4.16 In 2016, one-third of commercial payers used product preferencing for IVIG compared with just 17% for SCIG. In contrast, 53% of Medicare Advantage medical benefit administrators used product preferencing for IVIG compared with 20% for SCIG in 2016.16 This use of restricted formularies or fail-first policies are important options for managing Ig utilization and cost. However, requiring that patients switch to a different formulation from the one they are currently taking could lead to AEs.40
Care management can provide substantial economic and clinical benefits. Makanji et al reported on the impact of an Ig utilization-management and dose-optimization program in a regional health plan covering approximately 700,000 lives. The program involved comprehensive medical criteria with steps through alternative therapies when clinically appropriate, along with pharmacist-led interventions to recommend dose optimization based on adjusted body weight instead of actual body weight in obese adults. It also included pharmacist-led education and outreach to physicians.41-44
In the first year, the program produced a 17% overall reduction in total Ig spend, which translated to an estimated savings of approximately $1.4 million annually ($0.17 PMPM). Dose optimization led to an 8% savings ($606,235) over 1 year, primarily due to dosage changes in obese patients. Overall utilization also declined, and the paid amount for inappropriate indications decreased by 77%.41
One study of a care management program for 242 patients who received “high-touch” IVIG clinical management through a home infusion specialty pharmacy found a significantly lower rate of serious bacterial infections in the intervention group compared with a control group (n = 968) (4.13% vs 7.75%; P = .049). Patients received IVIG infusion in their homes or in ambulatory infusion suites. They also received a preinfusion risk assessment by a pharmacist to identify any comorbidities that might increase the risk of AEs; infusion monitoring by an Ig-specialized registered nurse, including individualized infusion rate protocols and patient education; regular clinical follow-up with a pharmacist to assess adherence and AE management; and financial counseling.45 There were no significant differences in treatment-related AEs or nonserious infections. There was, however, a 20% reduction in annual adjusted total medical costs ($109,476 vs $135,998; P = .002), primarily due to a shift in the site of care from outpatient to home.46
Payers are also using benefit design to better manage Ig costs. A study presented at the Academy of Managed Care Pharmacy’s 2018 annual meeting described the outcomes of a specialty channel management project that shifted IVIG coverage from the medical to the pharmacy benefit in a Medicaid managed care plan in Pennsylvania. Investigators analyzed claims data from July 1 to October 26, 2017, identifying 135 claims for different IVIG medications for 17 members. The data showed a significant cost-saving benefit of 70.2% (P = .014) when IVIG was managed under the pharmacy benefit.47 Of course, this could simply shift more of the cost to the patients depending on their copayment.
As noted earlier, Ig is often used off-label. Although many of those uses are clinically appropriate, some are not. For instance, a cost-minimization analysis of financial data related to treating patients with Guillain-Barré syndrome with IVIG or therapeutic plasma exchange (TPE), both of which have been found to be equally effective, found direct costs of IVIG therapy to be more than twice that of TPE ($10,330 vs $4638.)46
Finally, preauthorization requirements are nearly always used for Ig. These may include restricting Ig coverage to certain providers in certain specialties, such as immunology, oncology, and neurology19; restricting its use for specific indications with limited approval for off-label indications or acute conditions; and longer term approval for chronic conditions such as primary immunodeficiencies.48
Immunoglobulin accounts for the third greatest drug spend in commercial plans and the fourth under Medicare, despite the fact that less than 1% of the population covered requires it. It is used most often as a lifelong treatment for primary immunodeficiencies, a heterogenous class of immune-related conditions whose prevalence is increasing. However, it is also used for several other chronic and acute indications, some off-label. The total cost of Ig infusion depends on the type of delivery method used and the site of care. There are factors to be considered for both IVIG and SCIG. Numerous studies attest to the efficacy and cost savings of shifting IVIG to the home setting, and even shifting patients from IVIG to SCIG. In addition, surveys find that patients much prefer home delivery, with patient evaluations also finding a preference for SCIG. Payers have numerous options to ensure that Ig is used appropriately for the right patient in the right setting. These include site-of-care programs, education for providers and patients on the possibility of switching from IVIG to SCIG, preauthorization policies that restrict the use of Ig to certain specialties for specific indications, and shifting coverage from the medical to the pharmacy benefit. n
*Please note that currency has been converted to US dollars where necessary.
Author affiliation: Chief Operations Officer, NuFACTOR, Temecula, CA.
Funding source: This activity is supported by educational grants from CSL Behring LLC and Grifols.
Author disclosure: Ms Vaughan has the following financial relationships with commercial interests to disclose:
Advisory Board: Grifols
Authorship information: Drafting of the manuscript; critical revision of the manuscript for important intellectual content; and administrative, technical, or logistic support.
Address correspondence to: Lvaughan@nufactor.com.
Medical writing and editorial support provided by: Debra Gordon, MS.
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