1. Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by the degeneration of alpha motor neurons in the spinal cord which results in progressive proximal muscle weakness and paralysis [1]. The incidence of SMA ranges from 1 in 6,000 to 1 in 10,000 live births, and carrier frequency ranges from 1/40 to 1/60, making it the second most common fatal autosomal recessive disorder after cystic fibrosis [2,3].

In Greece, its prevalence is estimated at 3.3/100,000 and 1.5/100,000 according to Orphanet [4] and Kekou et al. 2020 [5], respectively. The debilitating nature and severity of the disease require a variety of healthcare resources, including frequent visits to medical practitioners and expensive treatments to increase life expectancy. Patients may have restricted access to early medication if SMA diagnosis is delayed for months or even years.

Various studies have been conducted worldwide in an effort to estimate the economic burden of SMA to the society as a whole [6-18]. To our knowledge, no study has been published in Greece delving into the economic burden of SMA.

Further, not many studies [19] have attempted to quantify the economic impact of introducing a reproductive carrier screening (RCS) program to the third-party payer’s budget as well. The purpose of the RCS is to inform women who are about to give birth on the likelihood of giving birth to a child who will develop SMA.

Reproductive choices of couples who have been informed of a positive result differ between countries [4, 5, 20, 21]. Few real-world studies have shown that a high proportion of couples do not proceed with the pregnancy [22-24] while in an Israelian study this percentage dropped to around 50% [25].

In Greece, a survey conducted in two hospitals among 533 women showed that 78% and 86% would not proceed with pregnancy in cases of lethal anomaly or developmental delay, respectively [26]. Real world Greek data from 88 pregnancies from a single hospital indicate an increase to this number to 96% and 100% for lethal anomalies and developmental delays, respectively [26].

The present study aims to present results regarding the socio-economic burden of SMA in Greece and specifically estimate the cost of illness (COI) and health-related quality of life (HRQoL) of patients with SMA. Further it attempts to assess the economic impact to the Greek National Health System from the implementation of an RCS program.

2. Methodology

A cross-sectional study was conducted between October to December 2022. An online questionnaire with 21 queries was developed to assess patients' healthcare resource use (HCRU) (i.e., inpatient admissions, outpatient visits, surgical procedures, laboratory investigations, imaging tests and concomitant medications), equipment and services required for patients' daily activities, socio-demographic factors as well as parents’/ caregivers’ loss of productivity and HRQoL. The questionnaire was reviewed and validated by members of the "95" Rare Alliance Greece, a Greek non-profit organization advocating for patients with rare diseases. Respondents' healthcare resource use was leveraged as input in the COI model while cost inputs were retrieved by publicly official sources.

A convenience sample of 19 families was identified while those eligible to participate in the study were patients diagnosed with SMA, and their main caregiver. The latter was responsible for the completion of the self-administered questionnaire. Participants were informed of the study objectives as well as confidentiality and anonymity of data and gave written consent to participate. The present study was conducted in accordance with the Declaration of Helsinki and the Greek legislation (Law 2328/1995, Presidential Decree 310/1996, Law 3603/2007, Law 2472/1997, Law 3471/2006), stating that there is no need for ethics approval in telephone and internet surveys such the one presented here. 

Following the queries focused on assessing the economic burden of SMA, the 36-item PedsQL™ Family Impact Module (FIM) was used to evaluate HRQoL of parents/ caregivers.  The 36-item PedsQL™ FIM Scales encompasses 6 scales measuring parent self-reported functioning: 1) physical functioning (6 items), 2) emotional functioning (5 items), 3) social functioning (4 items), 4) cognitive functioning (5 items), 5) communication (3 items), 6) worry (5 items), and 2 scales measuring parent reported family functioning; 7) daily activities (3 items) and 8) family relationships (5 items) [27]. Each item is scored on a five-point response scale, then converted to a 0 to 100 scale. A 5-point response scale is utilized (0 = never a problem; 4 = always a problem). Items are reverse-scored and linearly transformed to a 0–100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0), so that higher scores indicate better functioning (less negative impact). Scale scores are computed as the sum of the items divided by the number of items answered (this accounts for missing data).

2.1. Cost of illness analysis

A de novo COI model was developed to estimate the average annual economic burden of SMA in the Greek population from a societal perspective considering direct and indirect costs (productivity loss). The model adopted a prevalence approach and as such all prevalent cases in Greece were considered. Two approaches were explored to estimate the number of SMA patients; one using the prevalence value reported by Orphanet [4] and one using the prevalence recorded in 2020 by Kekou et al. [5]. The prevalence rates were then applied to the total number of the Greek population (10,432,481) [20] which estimated that 348 and 190 patients, were respectively expected to suffer from SMA in Greece. Moreover, based on an 1:11,000 incidence rate [5] it was estimated that approximately eight births of babies with SMA could be expected every year. The resources used, as reported in the questionnaires, were multiplied by the unit costs [21] to estimate the annual cost per patient and per population using 2022 as the reference year. An overview of the model structure is illustrated in Figure 1.

Figure 1 Model structure

2.1.1 Healthcare resource use inputs

Healthcare resource use of patients with the different types of SMA as reported by respondents is presented in Table 1. Overall, the healthcare resources with the highest usage for patients were visits to a healthcare practitioner, complete blood count testing, X-rays. Three hospitalizations were reported by patients during the previous year, each lasted approximately three days. The main reason of hospitalization was lower respiratory tract infections such as pneumonia and bronchitis, with pneumonia accounting for almost half of hospitalizations.

Table 1 Yearly healthcare resource use of patients with SMA

Furthermore, a number of patients required surgery of the spine (33%), tracheostomy (17%), gastrostomy (11%) and orthopedic operations (17%). Some health services that considered in the analysis such as physiotherapy, speech therapy, occupational therapy, hydrotherapy, and psychotherapy are not fully reimbursed in Greece. As outlined in Table 2, up to 100% of patients reported not receiving full reimbursement for their treatments, and in some cases (i.e., hydrotherapy), not being reimbursed at all.

Table 2 Percentage of reimbursement of specific therapies

Patients with SMA require additional resources such as consumables for tracheostomy, breathing devices and medications besides the SMA related treatment. Moreover, some patients may also need adjustments to their home, an elevator, or a vehicle for transportation to improve their daily management of the disease. It is also common for patients to visit hospitals and clinics at regular intervals to undergo various treatments, which contributes to the already high out-of-pocket costs. 

Last, more than half of respondents said that one of the two parents was unable to work because of the responsibility of caring for someone with SMA. The working parent had to take approximately 17 days off from work in order to assist with the activities.

2.1.2. Cost inputs

Cost inputs comprise of direct treatment acquisition and administration, direct monitoring and hospitalization (HCRU), out-of-pocket and indirect costs (productivity loss).

Treatment acquisition costs were based on the recommended dosing schemes as sourced from each treatment’s Summary of Product Characteristics (SPC) issued by European Medicines Agency (EMA) [28-30] and the published unit prices as sourced from the latest Drug price bulletin issued by the Greek Ministry of Health [31] (Supplementary Table 1).

Supplementary Table 1 Treatment dosing schemes and cost inputs

Administration costs were applied to the treatments that require to be administered by a physician or health professional with experience in the management of SMA and therefore the cost of a day-case hospital setting was charged (€80 per infusion [32]).

Monitoring and hospitalization costs were inserted into the model based on the annual frequency of use reported by respondents and the unit costs reflecting the official reimbursed prices by budget payer and the relevant DRGs. The aforementioned unit costs are illustrated in Supplementary Table 2. 

Supplementary Table 2 Unit costs of HCRU

Physiotherapy, speech therapy, occupational therapy, and psychotherapy are partially reimbursed by the Government, so patients do have to cover a portion of them, representing direct out-of-pocket payments, illustrated in Supplementary Table 3. Further a breakdown among activities comprising out-of-pocket costs for SMA patients can be shown in Figure 2.

Annual productivity loss for the working parent was calculated based on the daily wage of €56.7 as sourced from Hellenic Statistical Authority [33]. The annual productivity loss cost was estimated at €964.

Supplementary Table 3 Out-of-pocket costs

Figure 2 Percentage breakdown of out-of-pocket costs

2.2. Assessment of reproductive carrier screening program economic impact

We further aimed to evaluate the impact of the implementation of an RCS program into the healthcare system and specifically to the yearly budget. In Greece, 85,799 women were pregnant in 2021 [34]. We assumed that all women who are pregnant would undertake the RCS program and also that following screening, women with positive test results will terminate the birth.  Further, we assumed that the carrier frequency is 1/40 which was based on updated unpublished data from the Laboratory of Medical Genetics [35] leading to a possible detection of ~2,145 female carriers. In these cases, the father would also need to be screened aggravating the budget by another 2,145 tests. Moreover, using an incidence rate for SMA of 1:11,000 [5] it is estimated that approximately 8 births of babies with SMA would be avoided with the use of an RCS program.

The resources necessary for the implementation of the RCS program were assessed in the context of a massive screening for SMN1 exon 7 deletions in up to 40,000 individuals in a period of 12 months and are presented in Supplementary Table 4. For the equipment, instead of paying off its total cost within the first year, an approach was used whereby the repayment of the costs was split among four installments across four years.

To be as inclusive as possible, our analysis considered a first scenario using the least extreme value of 78% from the Greek literature [26] and a second scenario using the value of 50% [25], as the percentage of cases in which the pregnancy would be terminated following a positive result.

Supplementary Table 4 Estimated total costs of a reproductive carrier screening program

*Cost required for a massive screening for SMN1 exon 7 deletions in up to 40,000 individuals in a period of 12 months

3. Results

3.1. Cost of illness

Participants were 41 years old on average (SD = 11.86) (range: 9-55 years) and 61% were female. The main characteristics of participants are shown in Table 3.

Table 3 Demographic characteristic of the study participants

Cost of illness comprise of the summary of direct treatment acquisition and administration costs, direct monitoring and hospitalization costs, out-of-pocket and indirect costs. Overall, the average annual cost of SMA was estimated at €261,785 per patient in 2022. Subsequently, the average annual out-of-pocket and indirect costs per patient were €20,846 (Table 4) which represents the 8% of the average annual cost.

Table 4 Per patient cost breakdown

Based on the two population scenarios with either 348 or 190 SMA patients in Greece, average annual costs were estimated at €91,036,017 and €49,739,395, respectively (Table 5). 

Table 5 Cost breakdown extrapolated to the whole population (348 patients)

3.2. Health-related quality of life

The analysis indicated that the burden on the HRQoL of parents/ caregivers of SMA patients is high, with scores below 50 on most scales. “Worry” and “daily activities” scores were the lowest, while “cognitive functioning” scores were the highest (Table 6). It is evident that SMA contributes to the HRQoL burden of the families, even if parents of children without any health condition responded scores between 100 and 75.

Table 6 PedsQL TM FIM scores in different functioning categories

3.3. Economic impact of reproductive carrier screening program implementation

The implementation of the RCS program when considering the first scenario (78% of cases tested positive opt to stop pregnancy [26]) indicates that investing €1,871,922 per year to test all pregnant women would lead to cost-savings up to €167,181 per year (Table 7). After the fourth year, which is when the disbursement of the equipment stops, the annual cost-savings are projected to increase by an additional €100,000.

However, considering the second scenario (50% of cases tested positive opt to stop pregnancy [25]) indicates that RCS may not prove as cost-saving as possibly expected. This is probably due to accumulative costs of both the implementation of the RCS and the early administration of therapies in the pregnancies to be continued, bringing on additional costs of up to €564,804.

Table 7 Economic impact of a reproductive carrier screening program implementation

4. Discussion

To our knowledge this is the first study conducted in Greece measuring the COI and HRQoL of patients with SMA and estimating the economic impact of the implementation of an RCS program. Our results revealed a average annual economic burden of €261,785 per patient in 2022. Applying this figure to the prevalence rates sourced from Orphanet [4] and Kekou et al. [5] resulted to average annual costs of €91,036,017 and €49,739,395 across all affected patients in Greece, respectively. Out-of-pocket costs were also very high representing approximately 8% of the total expenditure which is translated to €41,693 on average per patient.

5. Conclusion

In conclusion, a considerable economic burden exists for both healthcare system and families of SMA patients. Additionally, there is a notable impact in the QoL of those caring for SMA patients. The implementation of an RCS program could also have a positive impact to the healthcare system budget, as our research indicates, but more research and pilot tests are needed to confirm these results.

ACKNOWLEDGMENTS 

The data collection for this study was supported by
unconditional grants from Astrazeneca Greece, Genesis Pharma and Takeda Hellas. No
funding was received for the preparation of this article. 

CONFLICT OF INTEREST 

Vasileios Kontogiannis, Mary Adamopoulou, Dimitris
Athanasiou, Georgia Moraiti and Maria Kalogeropoulou report receiving financial support
for the conduct of this study from Astrazeneca Greece, Genesis Pharma and Takeda
Hellas. Maria Kalogeropoulou, Mary Adamopoulou and Dimitris Athanasiou conceived
and designed the study. Maria Kalogeropoulou, Mary Adamopoulou, Dimitris
Athanasiou, Georgia Moraiti and Vasileios Kontogiannis designed the study
questionnaires. Vasileios Kontogiannis and Maria Kalogeropoulou analyzed the data and
all authors contributed to the interpretation of the findings. Jan Traeger-Synodinos,
Chrystallena Sofocleous and Kyriaki Kekou provided costing data for the reproductive
carrier screening program. Vasileios Kontogiannis and Marios Athanasios Loupas
drafted the first manuscript version and all authors commented on this version. Authors
state no conflict of interest. All authors read and approved the final manuscript.