Economic evaluation of subcutaneous versus intravenous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy: a real-life study

Abstract

Objectives

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired peripheral neuropathy of immunological origin with a clinical presentation and course that are extremely variable. The therapeutic approach generally includes corticosteroid drugs, intravenous immunoglobulins (IVIGs) or plasmapheresis alone or in combination as first line therapy, and immunosuppressants. In 2014 the Italian regulatory agency included subcutaneous immunoglobulins (SCIGs) in the list of off-label drugs reimbursed by the national health service. Our aim is to compare costs and outcomes of IVIG versus SCIG therapy.

Methods

Patients medical records and therapeutic plans were retrospectively analysed to collect data on IVIG treatments 1 year before the switch to SCIG, and after 1 year of treatment with SCIG. A budget impact analysis was conducted through resource identification and quantification, and healthcare and non-health care costs evaluation.

Results

13 of 34 patients affected by CIDP who were referred to our neurophysiopathological unit and treated with IVIG were switched to home-based SCIG. After 1 year of receiving SCIG, 12 patients remained neurologically stable and reported good outcomes. Considering the cost of IVIG (€30.97/g) and adding to this the direct and indirect healthcare costs, the total cost of IVIG treatment for the 12 patients in a year was €371 417.06, compared with the cost of SCIG (€51.57/g) for a total annual cost of €631 745.16, not including indirect costs.

Conclusions

We observe a higher cost for SCIG treatment versus IVIG, which is not in line with data in the literature. However, SCIGs offer some important safety benefits and improvements in patient quality of life.

Background

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired peripheral neuropathy of immunological origin with clinical presentation and course that are extremely variable. Patients usually present a generalised pattern with numbness and weakness in the upper and lower extremities and spontaneous pain which develops gradually over several weeks.¹ Some patients present with a progressive sensory ataxia; in other patients motor deficits predominate. Proximal and distal limbs are commonly affected in a roughly symmetrical pattern. Occasionally, however, the demyelinating neuropathy is focally accentuated, leading to focal or multifocal motor dysfunction with associated conduction blocks on electrophysiological testing. The causes of CIDP are attributed to immune mechanisms. During active disease, pathological study of affected nerve roots and trunks shows inflammation and stripping of the myelin sheaths from the axons by macrophages. The inflammation is probably due to an autoimmune process.²

CIDP has a prevalence of 4–9 cases per 100 000 adults. In the absence of treatment the disease progresses, leading to about 30% of patients having to depend on a wheelchair for their mobility. However, early diagnosis and treatment can help prevent disability and improve functional recovery.³

The therapeutic approach generally includes corticosteroids drugs,⁴ intravenous immunoglobulins (IVIGs) or plasmapheresis⁵ alone or in combination as first-line therapy. When first‐line treatments are inadequate, neurologists often prescribe immunosuppressant or other immunomodulatory agents, that is, cyclophosphamide or rituximab in severe persistently unresponsive cases.

IVIG may be used as a first-line therapy; a Cochrane systematic review of five trials, including a total of 235 participants, concluded that a single course of IVIG significantly reduces disability and weakness.⁶ The IV line allows the administration of large volumes of IGs (which in an average patient vary between 400–600 mL) and, considering the IG half-life, with a frequency of 3 or 4 weeks. However, this type of therapy requires good venous access, can sometimes cause serious side effects (nausea, headache, fatigue, etc) and is associated with hospital costs.⁷

In recent years subcutaneous immunoglobulins (SCIGs) have been introduced. Compared with intravenous administration, SCIGs have the advantage of fewer side effects and home self-administration. According to Italian law 648/1996, the Italian Agency for Medicines (AIFA) included SCIGs in the list of medicines off-label reimbursed by the Italian National Health Service (INHS), for patients with CIDP in which it is appropriate to continue treatment already started subcutaneously (Agenzia Italiana del Farmaco⁸).

In May 2018, the European Commission granted the marketing authorisation of Hizentra as the first and only SCIG for maintenance therapy in patients with CIDP, after stabilisation with IVIG. Approval was based on data obtained from the phase III PATH (Polyneuropathy And Treatment with Hizentra) study, the largest randomised placebo-controlled clinical trial in CIDP patients.⁹ This represents an important step forward in supporting patients with CIDP, as they no longer need to go to an infusion centre or a hospital but have the possibility to opt for a flexible self-administration solution, which allows them to choose the timing, the place and the scheme that best suits their needs. However, the quantities that can be infused subcutaneously are significantly lower (maximum 20 mL per hour per site as tolerated) than those administered IV, so this method of treatment requires a weekly frequency through multiple injection sites.

Recently, a new therapeutic modality, that combines the main advantages of previous therapies, was developed. It enables monthly SC administration at a single site (compared with IVIG administered at one site on a monthly basis, and SCIG administered at multiple sites on a weekly basis). The flow and distribution of SCIG to the vasculature is impeded by the glycosaminoglycan hyaluronan in the extracellular matrix, which limits the infusion rate and volume per site, necessitating frequent infusions and multiple infusion sites. The new strategy involves preceding the subcutaneous infusion of IgG with an infusion of hyaluronidase, an enzyme that catalyses depolymerisation of hyaluronan; this results in enhanced drug delivery by increasing dispersion and absorption of IgG from the subcutaneous tissues, allowing larger volumes to be infused in each infusion site.¹⁰ The ease of self-administration of the new SC therapeutic treatment scheme favours better adherence to therapy and brings long-term clinical benefits along with reduced concomitant infections.

The “Antonio Cardarelli” hospital is one of the 11 regional reference centres for rare diseases in the Campania region; in particular, it is one of the eight regional centres for the care of patients with CIDP. Given the growing interest in SCIG and the strong impact of chronic inflammatory diseases on the healthcare system, we considered it was important to evaluate, in a real-life setting, the advantages and disadvantages of the two types of administration and conduct a budget impact analysis (BIA).

The aim of this study was to evaluate the budgetary implications of using SCIG relative to IVIG in patients with CIDP. The BIA is important as part of a comprehensive economic evaluation of a new health technology.¹¹

Methods

A retrospective study was conducted in patients diagnosed with CIDP who were referred to the neurophysiopathological unit at the “Antonio Cardarelli” hospital, who had hospital-based IVIG and were switched to home-based SCIG.

A survey of the regulatory context of IG and of the evidence available in the literature on efficacy and safety was carried out and a budget impact analysis was developed in order to evaluate the impact of introducing SCIG into the current CIDP treatment and compare the costs.

AIFA monitoring registers have proven to be a valid tool for estimating patients and obtaining clinical information. Thirty-four patients in our hospital were receiving treatment with IVIG and registered on the AIFA platform; 13 of them were selected to switch to SCIG therapy. The shift from IVIG to SCIG was due to fluctuations in clinical response (wear-off) and the patient’s desire for greater independence from hospital care.

The patients medical records were examined, collecting data on the treatment with IVIG in the year preceding the shift. The data of interest concerned the type of IG administered, the dosage and the interval between administrations, and the number of hospital admissions.

Subsequently, the SCIG therapeutic plans, uploaded on the regional computerised platform (SANI.A.R.P.), were consulted, considering the supplies made by the competent local pharmaceutical service and evaluating the type of SCIG prescribed, the dosage, and the interval between administrations.

The economic evaluation process compares the therapy with IVIG versus SCIG, taking into consideration the direct and indirect costs. The direct costs include the costs of the drug, the infusion devices, the time spent by neurologists, nurses and hospital pharmacists, the costs of laboratory tests and the general overhead costs, the costs incurred by the patient and caregivers for transport, and parking. The indirect costs, on the other hand, relate to the loss of productivity at work due to the absence caused by the patient’s illness and any caregivers. The hospital costs of immunoglobulins are obtained from the So.Re.Sa. S.p.A. (Regional Health Society). The direct and indirect costs are defined on the basis of expert opinions and research hypotheses.

Results

Thirteen patients (nine women and four men with an average age of 56±15 years) referred to the neurophysiopathological unit at the “Antonio Cardarelli” hospital receiving treatment with IVIG were selected to switch to SCIG therapy. After 1 year of SCIG treatment, the Inflammatory Neuropathy Cause and Treatment (INCAT) overall disability sum score and the Medical Research Council (MRC) Muscle Sum Score were examined; 12 patients remained neurologically stable, and only one patient returned to IVIG therapy after the symptoms worsened.

Healthcare and no healthcare resource utilisation differs markedly between SCIG and IVIG options. For the economic evaluation, we started from the analysis of the hospital costs of IVIG obtained from the So.Re.Sa. S.p.A. With the aim of carrying out a more balanced economic analysis, the use of the medicinal product Venital is not considered as it was provided, in the period considered, to the hospital at zero cost according to the National Plasma Program. The choice was to assume that the medicinal product Privigen (IVIG1) was administered to all patients under examination, at a cost of €30.97/g.

Subsequently, the direct and indirect costs associated with IV therapy were considered.

Direct costs include healthcare costs, such as the cost of hospital staff, calculated by averaging the time spent by doctors, nurses and pharmacists at each patient hospital access (table 1); consumables, set at €3 per access; and laboratory tests performed by patients in 1 year (table 2). To these costs we add general overhead costs quantified at 20% by the internal management control, which include, for example, employee benefits, administrative staff, the salary of the chief executive, utilities, office supplies, insurances, building and equipment operation and maintenance.

Table 1.

Hospital staff cost

Hospital staff	Time spent for patient (mins)	Hospital staff cost for each patient access
Doctors	10	€10.15
Nurses	40	€17.91
Pharmacists	10	€9.08
Total		€37.14

Table 2.

Laboratory and instrumental tests costs

Laboratory test	No. tests/year for patient	Test cost (€)	Total cost for patient in a year
CBC	4	€3.17	€12.68
Transaminase	4	€2.02	€8.08
Azotemia	4	€1.13	€4.52
Glycaemia	4	€1.17	€4.68
Electrophoresis	4	€4.23	€16.92
Electromyography	2	€43.89	€87.78
IgA	1	€14.97	€14.97
Blood type	1	€1.00	€1.00
Ag	1	€32.70	€32.70
			€183.33

Ag, albumin/globulin rate; CBC, complete blood count; IgA, immunoglobulin A.

Moreover, another direct but non-medical cost is the parking cost incurred by the patient and family members, quantified at €6 per access.

From consultation of the medical records, the number of accesses during the year was assessed for each patient and the total direct costs for the 12 patients, equal to €20 732.06, were calculated (table 3).

Table 3.

Direct costs due to IVIG therapy

Patients	No. of hospital accesses due to IV therapy	Hospital staff cost	Laboratory tests cost	Consumable	Hospital cost (20%)	Parking	Total direct costs (IVIG cost not included)
1	27	€1002.78	€183.33	€81.00	€253.42	€162.00	€1682.53
2	11	€408.54	€183.33	€33.00	€124.97	€66.00	€815.84
3	33	€1225.62	€183.33	€99.00	€301.59	€198.00	€2007.54
4	23	€854.22	€183.33	€69.00	€221.31	€138.00	€1465.86
5	16	€594.24	€183.33	€48.00	€165.11	€96.00	€1086.68
6	17	€631.38	€183.33	€51.00	€173.14	€102.00	€1140.85
7	40	€1485.60	€183.33	€120.00	€357.79	€240.00	€2386.72
8	12	€445.68	€183.33	€36.00	€133.00	€72.00	€870.01
9	20	€742.80	€183.33	€60.00	€197.23	€120.00	€1303.36
10	43	€1597.02	€183.33	€129.00	€381.87	€258.00	€2549.22
11	38	€1411.32	€183.33	€114.00	€341.73	€228.00	€2278.38
12	54	€2005.56	€183.33	€162.00	€470.18	€324.00	€3145.07
Total		€12 404.76	€2199.96	€1002.00	€3121.34	€2004.00	€20 732.06

IVIG, intravenous immunoglobulin.

The indirect costs were calculated by taking into consideration the loss of productivity at work for patients and caregivers. We started by dividing the average salary (€19 900) and working hours (1718) of an Italian citizen in a year.¹² The data obtained were multiplied by six (average daily working hours) obtaining a daily productivity loss of €69.7 and a total of €46 559.60 for the 12 patients and their caregivers.

Therefore, considering the cost of the IVIG and adding to it the direct and indirect costs, the total cost of IVIG treatment for the 12 patients in a year is €371 417.06 (table 4).

Table 4.

Total costs due to IVIG therapy

Patients	Sex	Age	IVIG	Number of accesses	Gram IVIG	Cost IVIG	Total direct costs	Total indirect costs	Total costs
1	F	73	IVIG1	27	675	€20 904.75	€1682.53	€3763.80	€26 351.08
2	M	57	IVIG1	11	385	€11 923.45	€815.84	€1533.40	€14 272.69
3	F	35	IVIG1	33	1040	€32 208.8	€2007.54	€4600.20	€38 816.54
4	M	67	IVIG1	23	760	€23 537.2	€1465.86	€3206.20	€28 209.26
5	M	45	IVIG1	16	705	€21 833.85	€1086.68	€2230.40	€25 150.93
6	M	54	IVIG1	17	510	€15 794.7	€1140.85	€2369.80	€19 305.35
7	F	47	IVIG1	40	1260	€39 022.2	€2386.72	€5576.00	€46 984.92
8	M	64	IVIG1	12	360	€11 149.2	€870.01	€1672.80	€13 692.01
9	M	34	IVIG1	20	930	€28 802.1	€1303.36	€2788.00	€32 893.46
10	F	79	IVIG1	43	600	€18 582.0	€2549.22	€5994.20	€27 125.42
11	M	74	IVIG1	38	975	€30 195.75	€2278.38	€5297.20	€37 771.33
12	M	38	IVIG1	54	1620	€50 171.4	€3145.07	€7527.60	€60 844.07
Total				334	9820	€304 125.4	€20 732.06	€46 559.6	€371 417.06

IVIG, intravenous immunoglobulin.

The same path is followed for subcutaneous immunoglobulins. Of the 12 patients, 10 were being treated with the Hizentra specialty at a cost of €48/g, and only two were being treated with Hyqvia at a cost of €51.57/g.

The amount of IG administered by patients in 1 year are calculated from the consultation of the therapeutic plans. The prescribed SCIG dose differs from that of IVIG, because there are pharmacokinetic differences between IVIG and SCIG, and incremental adjustments are often required based on clinical status.

The costs of the drug are added to the other direct costs, but the parking cost and the indirect costs are not calculated for the SCIG treatment as it is not necessary for the patient to go to the hospital to receive the therapy.

The number of hospital accesses for SCIG patients in 1 year are generally four, which are necessary for routine checks. The direct costs include the costs of the neurologist (€10.15 per access), the cost of the laboratory test carried out twice a year (€11.72×2), and the cost of the electromyography performed once a year (€43.89). The costs of the infusion pumps and the infusion lines necessary for the treatment are not considered, as they are provided free of charge by the pharmaceutical company with the medicinal specialty. In addition, the total cost for the 12 patients for 1 year of therapy with SCIG is therefore equal to €631 745.16, much higher than the cost of therapy with IVIG (table 5).

Table 5.

Total costs due to SCIG therapy

Patients	Sex	Age	SCIG	Number of accesses	Gram SCIG	Cost SCIG	Direct costs	Total costs
1	F	73	Ig 20% liq	4	1040	€49 920.00	€107.93	€50 027.93
2	M	57	Ig 20% liq	4	520	€24 960.00	€107.93	€25 067.93
3	F	35	Ig 20% liq	4	1040	€49 920.00	€107.93	€50 027.93
4	M	67	Ig 20% liq	4	1040	€49 920.00	€107.93	€50 027.93
5	M	45	Ig 20% liq	4	1040	€49 920.00	€107.93	€50 027.93
6	M	54	Ig 20% liq	4	520	€24 960.00	€107.93	€25 067.93
7	F	47	Ig 20% liq	4	1560	€74 880.00	€107.93	€74 987.93
8	M	64	Ig 20% liq	4	730	€35 040.00	€107.93	€35 147.93
9	M	34	Ig 10% rHuPH20	4	1300	€67 041.00	€107.93	€67 148.93
10	F	79	Ig 20% liq	4	973	€46 704.00	€107.93	€46 811.93
11	M	74	Ig 20% liq	4	1040	€49 920.00	€107.93	€50 027.93
12	M	38	Ig 10% rHuPH20	4	2080	€107 265.00	€107.93	€107 372.93
Total						€630 450.00	€1295.16	€631 745.16

rHUPH20, recombinant human hyaluronidase; SCIG, subcutaneous immunoglobulin.

Discussion

In this retrospective analysis we assessed the economic impact for the INHS related to the use of SCIG as a substitute for IVIG therapy. From the analysis of our real life data, made available by the AIFA registers, the computerised medical records, the Saniarp therapeutic plans and by comparison of the purchase price, a higher cost for the national health system was configured for the treatment of CIDP with SCIG versus IVIG, data that are not in line with the reference literature.

European economic studies performed in Sweden,¹³ Germany,¹⁴ the UK¹⁵ and France¹⁶ reported that home-based SCIG was 25–75% less costly for the healthcare system than hospital-based IVIG, due to the lower cost of SCIG compared with IVIG in these countries.

The results may have been the same as in other countries if the immunoglobulins cost had not been included and focused specifically on supplies and human resources.

Also in a previous Italian study,^{17 18} Cocito et al, comparing the direct and indirect costs related to the use of SCIG versus IVIG in CIDP patients, concluded that the overall costs per patient amounted to €49 534.75 (SCIG) and € 50 895.73 (IVIG), with a minimum saving in favour of SCIG of €1360.98.

Our different results are due to a higher drug cost per gram for SCIG (€48 and €51.57) compared with IVIG (€30.97), and the need to use, in our real life setting, a higher dose (g) of SCIG to achieve the desired clinical response, which is not compensated by the higher direct and indirect costs for IVIG compared with SCIG.

Study limitations concern the non-quantification of intangible costs and subjective factors such as quality of life, leisure time and patient’s satisfaction for SCIG compared with in-hospital IVIG therapy. In fact, SCIG therapy, although generally requiring a higher frequency of administration, offers important benefits as it reduces adverse events and allows a stable serum concentration of immunoglobulin levels to be achieved. Studies have shown that the administration of SCIG, not requiring hospital access, does not interfere with patients’ work activities and eliminates the need to be on long waiting lists; moreover, patients are less anxious at home than in hospital and they have more autonomy.^{18 19}

Focusing on quality of life and treatment satisfaction, Braine and Woodall reported a cross-sectional study in 16 patients with multifocal motor neuropathy, including nine treated with IVIG in hospital and seven switched to self-administered SCIG treatment.²⁰ A Treatment Satisfaction Questionnaire Medication (TSQM) was applied in conjunction with a 30 min interview, and the treatment satisfaction assessed was overall higher in the SCIG group. Time savings, greater treatment flexibility, normalisation of living conditions, stabilisation of the treatment effect, reduced side effects and a general feeling of self-control were the main topics reported after the switch to SCIG therapy.

The available data indicate that treatment with self-administered SCIG in CIDP leads to a global improvement in patient quality of life, representing a therapeutic opportunity that reconciles the needs of patients. Although the costs are higher, it is appropriate to consider that the possibility of performing home therapy favours adherence to the therapeutic regimen, improves clinical benefits and in the long term could result in an optimisation of health expenditure.

Conclusions

Information regarding rare diseases is often difficult to find and clinical and economic evaluations necessary for drug governance may be lacking. The information provided by our study has allowed a fruitful collaboration with doctors to deepen these assessments regarding CIDP treatments with IG. The real-life economic analysis showed a greater expense for the national health system in the treatment with SCIG compared with IV therapy. This compares to an improvement in patient quality of life, for whom subcutaneous therapy represents an important therapeutic opportunity. The emerged consideration could be configured as a basis for structuring a budget-impact analysis and for the drafting of a therapeutic diagnostic pathway for CIDP.

What this paper adds.

What is already known on this subject

• Information regarding rare diseases is often difficult to find, and clinical and economic evaluations necessary for drug governance may be lacking. The literature on this subject reports a higher cost for intravenous immunoglobulin (IVIG) therapy than for subcutaneous immunoglobulin (SCIG) therapy. However, we observed a high cost of SCIG therapy and decided to conduct this study.

What this study adds

• The information provided by our real-life economic analysis showed a greater expense for the national health system in the treatment with SCIG compared with IVIG. The emerged consideration could be configured as a basis for structuring a budget-impact analysis and for the drafting of a therapeutic diagnostic pathway for chronic inflammatory demyelinating polyneuropathy in a wider setting.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. -

Ethics statements

Patient consent for publication

Not required.