Cost-effectiveness analysis of defibrotide in the treatment of patients with severe veno-occlusive disease/sinusoidal obstructive syndrome with multiorgan dysfunction following hematopoietic cell transplantation in Spain

Abstract

Aims

This study evaluated cost-effectiveness of defibrotide vs best supportive care (BSC) for the treatment of hepatic veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) with multiorgan dysfunction (MOD) post-hematopoietic cell transplantation (HCT) in Spain.

Materials and methods

A two-phase Markov model, comprising a 1-year acute phase with daily cycles and a lifetime long-term phase with annual cycles, was adapted to the Spanish setting. The model included a cohort of patients with severe VOD/SOS (defined as VOD/SOS with MOD) post-HCT. For the acute phase, efficacy and VOD/SOS-related length of stay were obtained from a phase 3 defibrotide study (NCT00358501). VOD/SOS-related hospital stays were 7.5 and 23.2 days in defibrotide-treated and BSC patients, respectively. Defibrotide-treated patients spent 30% of their stay in the intensive care unit vs 60% in BSC patients. Assumptions for the long-term phase and utility values were obtained from the literature. Costs were from the Spanish Health System perspective (€2019). Defibrotide cost was based on 25 mg/kg/day over 17.5 days, using local expert opinion. Life-years (LYs), quality-adjusted LYs (QALYs), and costs were estimated over a lifetime horizon, applying a 3% discount rate for costs and outcomes. Sensitivity analyses assessed the robustness of the results.

Results

Defibrotide produced an additional 1.214 QALYs and 1.348 LYs vs BSC, with a total cost of €33,708 more than BSC alone. However, defibrotide resulted in savings up to €16,644/patient for cost of hospital stay. Difference between costs and effective measures led to ratios of €27,757/QALY and €25,007/LY gained. Additional hospital stays had the greatest influence on base-case results. Probabilistic analysis confirmed the robustness of the deterministic results.

Limitations

Limitations include use of historical controls and assumptions extrapolated from the literature.

Conclusions

This cost-effectiveness model, adapted to the Spanish setting, showed that defibrotide is a cost-effective alternative to BSC alone in patients with severe VOD/SOS post-HCT.

Keywords:

• Defibrotide
• cost-effectiveness
• Spain
• sinusoidal obstruction syndrome
• veno-occlusive disease
• multiorgan dysfunction

JEL CLASSIFICATION CODES:

• I00
• E20

Introduction

According to the World Health Organization, >50,000 hematopoietic cell transplantation (HCT) procedures are performed annually, worldwide, with the number increasing each year¹. HCT has become a standard treatment for a variety of nonmalignant and malignant diseases, but it is expensive and can also result in significant complications^2,3. Post-HCT complications, such as veno-occlusive disease or sinusoidal obstructive syndrome (VOD/SOS) or graft-versus-host disease, are major contributors to the high costs of HCT following transplantation⁴. VOD/SOS, an unpredictable and potentially life-threatening condition, is one of the primary causes of HCT-related mortality^5,6. Without treatment, patients with severe VOD/SOS may die within days or weeks of an expensive transplant procedure, often in an intensive care setting⁷. VOD/SOS is estimated to have an average incidence of 14%, but incidence of VOD/SOS has been reported to be as high as 40% in high-risk patients^6,8. A variety of factors can impact the risk of developing VOD/SOS, including conditioning regimen, type of HCT, age, and preexisting liver disease⁹.

Although VOD/SOS pathophysiology is not fully understood, pathogenesis is initiated by activation of sinusoidal endothelial cells and damage to hepatocytes caused by the buildup of toxic metabolites generated by HCT conditioning regimens¹⁰. These insults induce a procoagulant, proinflammatory, and antifibrinolytic environment that results in loss of endothelial cell structure and subsequent sinusoidal narrowing and obstruction⁵.

Clinically, VOD/SOS is characterized by hepatomegaly, jaundice, weight gain, and ascites. Severity of VOD/SOS ranges from mild disease to severe disease associated with multiorgan dysfunction (MOD)⁶. Severe VOD/SOS with MOD has been associated with a mortality rate >80% if treated with supportive care alone. Therefore, there is a particular interest in effective approaches to prevent and/or treat severe VOD/SOS⁵.

Several symptomatic measures, such as oxygen therapy, analgesia, paracentesis, and thoracentesis, as appropriate, can be used to reduce discomfort caused by massive ascites or pleural effusions¹¹. In cases of suspected VOD/SOS, therapeutic interventions, such as optimizing hydroelectrolytic balance and restricting the supply of sodium by diuretics or using hemodialysis or hemofiltration when fluid accumulation and renal failure cannot be controlled, may be used. In some cases, VOD/SOS has been resolved with an intrahepatic portosystemic shunt or, more rarely, with liver transplantation¹². In addition, defibrotide, a mixture of predominantly single-stranded polydeoxyribonucleotides, is approved in Europe for the treatment of severe hepatic VOD/SOS following HCT in adults and pediatric patients aged >1 month¹³. In vitro studies suggest that the mechanism of action of defibrotide involves two distinct elements: the protection of endothelial cells and the restoration of thrombotic-fibrinolytic balance¹³. The efficacy and safety of defibrotide for the treatment of VOD/SOS post-HCT have been demonstrated in a number of studies^14–17. In a phase 3 study of defibrotide in patients with VOD/SOS with MOD, day 100 survival was 38% in defibrotide-treated patients and 25% in historical controls (23% estimated difference between groups; 95.1% confidence interval [CI] = 5.2–40.8; p = 0.0109, using a propensity-adjusted analysis)¹⁴.

Defibrotide is designated as an orphan medicine by the European Medicines Agency (EMA) and was approved under exceptional circumstances due to the rarity of hepatic VOD/SOS¹³ and, thus, collection and evaluation of additional data on efficacy and safety are ongoing¹⁸. In the US, defibrotide received orphan drug status and FDA approval based on the results of two prospective trials and an expanded access study¹⁹.

Although the safety and efficacy of defibrotide in patients with VOD/SOS post-HCT is established, data on cost-effectiveness of defibrotide in Europe is needed in order to inform the health technology assessment process. This study sought to determine the cost-effectiveness of defibrotide for the treatment of patients who develop severe VOD/SOS (defined as VOD/SOS with MOD) post-HCT in the Spanish setting.

Methods

Model structure

A Markov model, with an acute phase (until year 1, with daily cycles) and a long-term phase (from year 1 to the end of time horizon, with annual cycles), was adapted to the Spanish setting²⁰. To ensure that the adaptation of the model fit the current clinical practice in Spain, all the inputs and assumptions were validated by a panel of six experts.

The acute phase consisted of three health states: severe VOD, complete response (CR), and death. The long-term phase had two states, since the severe VOD and CR states were merged into the ‘survival state’ (Figure 1).

Figure 1. Model diagram. Abbreviations. VOD/SOS, veno-occlusive disease/sinusoidal obstruction syndrome; MOD, multiorgan dysfunction; CR, complete response.

The time horizon of the analysis included the entire life of the patient (lifetime) with a theoretical maximum of 100 years (99.8% of the patients would have died). A discount rate of 3% was applied for both costs and future effects, in accordance with published recommendations on the evaluation of health technologies in Spain^21,22.

The model compared estimated costs and health outcomes for defibrotide vs best supportive care (BSC) alone. The results of the cost-effectiveness analysis were expressed using the incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) of defibrotide vs BSC alone.

Study population and compared alternatives

The study population of the analysis replicated the cohort included in the phase 3 clinical study of defibrotide. The study included 102 patients (44 children and 58 adults; mean age of 26 years) with severe VOD/SOS who received 25 mg/kg of defibrotide (in addition to BSC) compared with 32 historical controls (identified from the clinical records of 6,867 HCT patients who received BSC alone). Severe VOD/SOS was defined as VOD/SOS with MOD (renal and/or pulmonary dysfunction by day 28 post-HCT)¹⁴. In the phase 3 study, efficacy analyses were based on propensity score-adjusted estimators; propensity scores provided an adjustment for prognostic factors that may have been unbalanced between treatment groups.

Efficacy parameters

The Markov model used transition probabilities calculated using raw data from the phase 3 clinical study on overall survival (OS) and probability of reaching CR.

The Kaplan-Meier (KM) curves for CR and OS were both extrapolated to day 365 to complete the time horizon for the acute phase. Subsequently, all patients who either reached CR or were still alive at day 365 entered the ‘survival state’ of the long-term phase.

Acute phase

For the acute phase, an area under the curve approach was used to model the transition between health states based on parametric curves and assuming that patients who reached CR did not have a subsequent recurrence of severe VOD/SOS.

Survival data from the phase 3 study were available up to days 150 and 94 for patients treated with defibrotide and BSC, respectively. A semiparametric approach was found to be the most appropriate method to respond to the plateau observed in the KM curves from day 100 to 150 and from day 69 to 94 in the defibrotide and control arms, respectively. Therefore, the available KM data were incorporated into the noted ‘plateau’ of the curves of each treatment arm, and the remaining time until day 365 was extrapolated using an exponential function and the hazard ratio (HR) for the ‘plateau’ of each survival curve (HR = −0.0012 for defibrotide and historical controls; Supplementary Figure S1).

In the phase 3 study, data on CR were available up to days 137 and 97 for patients treated with defibrotide and BSC, respectively. Similar to the survival data, a ‘plateau’ in the time to CR was observed from day 101 to 137 in the defibrotide arm and from day 50 to 97 for the control arm. In order to calculate the time-dependent cycle probabilities of achieving CR, the KM curve of ‘1 – CR’ from the phase 3 study was scanned and inverted (Supplementary Figure S2).

The KM curves for ‘1 ‒ CR’ only included patients who reached CR and were alive at the end of the study and did not account for the OS rate. Therefore, the ‘1 ‒ CR’ curve was adjusted to incorporate OS data and ensure that the proportion of responding patients did not exceed the proportion of surviving patients. As an example of the adjustment, the proportion of patients with a CR by day 100 was 23.54% and the proportion of survivors by day 100 was 37.89%, so the ratio used to adjust the CR curve (for the example at day 100) was: 23.54% × 37.89% = 9.92%. Since data were only available for day 100, this ratio was used throughout the acute phase, which spanned from day 1 to day 365. These adjustments ensured that the proportion of patients with a CR at day 100 was consistent with the results of the phase 3 study.

Long-term phase

A literature review was performed to develop an estimate of the life expectancy of patients who recovered from VOD/SOS post-HCT. The literature review identified a study published in 2011 by Remberger et al., which evaluated survival in 953 patients who underwent allogeneic HCT during four different time periods (1992–1995, 1996–2000, 2001–2005, and 2006–2009)²³. In order to capture any recent improvements post-HCT while also capturing data from the longest period of observation, the survival curves of the first (1992–1995) and the last period (2006–2009) of the study were combined into a single curve and used to model the first 9 years of the long-term phase (year 2 to year 10).

For the following years (year 11 to end of life), Spain’s general population survival data (Instituto Nacional de Estadística 2019) were used. However, patients who have undergone HCT tend to have a shorter life expectancy compared to the general population. To account for this, the panel of experts agreed to adjust the general population survival data using the relative survival of 0.995 reported by Nivison-Smith et al.²⁴.

Safety parameters

It was assumed that treatment-related adverse events (AEs) did not develop after a patient was discharged from the hospital. Thus, treatment-related AEs are reflected in the hospital stay and were not considered to contribute to an extension of the hospital stay or additional costs. Therefore, the panel of experts agreed not to include AEs in the model.

Cost inputs

The analysis was carried out from the perspective of the Spanish Health System, so only direct health costs were considered (these included pharmacologic costs and costs of extended hospital stay due to severe VOD/SOS). All costs were expressed in Euros for the year 2019.

Pharmacologic costs of defibrotide were calculated based on an ex-factory price of €426, considering a mean weight of 53.7 kg based on data from the phase 3 study and, for the base case, assumed optimization of defibrotide vials. Based on prevailing clinical practice in Spain, the panel of experts determined the mean duration of defibrotide treatment was 17.5 (range = 14–21) days. Administration costs were not considered separately but were included in the cost of hospital stay since defibrotide is administered during the management of severe VOD/SOS.

To estimate costs associated with extended hospital stay due to the development of severe VOD/SOS, the average length of stay (LoS) of patients undergoing HCT was established. LoS was obtained from the Spanish National Hospital Discharge Database (SNHDD) for groups related to the diagnoses 803 (allogeneic HCT) and 804 (autologous HCT) and weighted by VOD/SOS incidence since VOD/SOS is more frequently associated with allogeneic HCT than autologous HCT²⁵. An average LoS of 38.83 days was established for patients undergoing HCT. Secondly, extended hospital stay costs due to severe VOD/SOS were calculated based on the time to CR reported in the phase 3 study; mean time to CR was 46.3 and 62.0 days in the defibrotide and historical control groups, respectively^7,14. Extended hospital stay due to severe VOD/SOS was defined as the difference between the mean LoS due to HCT and the time to CR for the corresponding treatment group (Figure 2). Table 1 shows the calculated values for extended hospital stay due to severe VOD/SOS (7.5 and 23.2 days in the defibrotide and BSC arms, respectively).

Figure 2. Use of resources, unit costs, and cost per cycle for the health states of the model. Abbreviations. HCT, hematopoietic cell transplantation; VOD/SOS, veno-occlusive disease/sinusoidal obstruction syndrome; CR, complete response; BSC, best supportive care.

Table 1. Summary of the costs associated with extended hospital stay due to severe VOD/SOS.

	Defibrotide + BSC		BSC alone
Extended hospital stay, days	7.5		23.2
	ICU	Transplant unit	ICU	Transplant unit
Unit type distribution, %	30	70	60	40
Unit cost (MBDS-H),^a €	1,254.60	909.80	1,254.60	909.80
Cost per extra day of stay, €	1,013.23		1,116.68

Abbreviations. VOD/SOS, veno-occlusive disease/sinusoidal obstruction syndrome; BSC, best supportive care; ICU, intensive care unit; MBDS-H, Mínimo Básico de Datos – Hospitalización.

^aData obtained from the Ministerio de Sanidad Consumo y Bienestar Social²⁵.

Finally, the cost associated with extended hospital stay due to severe VOD/SOS was estimated based on the time spent in each hospital unit. The panel of experts considered the proportion of time spent in the intensive care unit (ICU) and transplant unit (recovery ward) to be different for patients treated with BSC vs defibrotide. The panel estimated that patients treated with BSC spent 60% (sensitivity analysis range = 40–80%) of their time in the ICU and 40% (sensitivity analysis range = 20–60%) of their time in the transplant unit, while defibrotide-treated patients were estimated to spend 30% (sensitivity analysis range = 20–40%) and 70% (sensitivity analysis range = 60–80%) of their time in the ICU and transplant units, respectively.

Based on these proportions and the unit costs per day obtained from the SNHDD²⁵, the costs per extended hospital stay due to severe VOD/SOS were calculated (Table 1).

Utilities

For the cost-effectiveness analysis, the literature was searched for utility values; these values represent the impact on quality-of-life associated with a particular health state on a scale of 0 (death) to 1 (perfect health). However, no utilities data specific to patients with VOD/SOS post-HCT were identified. Therefore, utility values from studies with patient populations that approximate the VOD/SOS post-HCT population were used.

In a study of patients with hepatic insufficiency prior to liver transplantation with Model for End-Stage Liver Disease >30, a population with comorbidities and a survival expectancy similar to patients with severe VOD/SOS, a utility of 0.208 was reported²⁶. Hence, this utility value was used to approximate the severe VOD/SOS health state. For patients with severe VOD/SOS who reached CR, it was assumed that there was no continuing impact on quality-of-life after resolution of VOD/SOS; thus, the utility would be similar to that of the general population (adjusted for age). In the absence of Spanish data, the age-dependent utilities reported in Szende et al.²⁷ were used. Table 2 summarizes the utility values included in the model.

Table 2. Utility values.

Health condition	Utility	Range	Reference
Utility in ‘CR state’ according to age, years			Szende et al.^27
18–24	0.951	0.945, 0.957
25–34	0.936	0.944, 0.928
35–44	0.919	0.925, 0.913
45–54	0.898	0.906, 0.890
55–64	0.874	0.884, 0.864
65–74	0.835	0.849, 0.821
≥75	0.756	0.758, 0.754
Severe VOD/SOS utility	0.208	0.166, 0.250	Aberg et al.^26

Abbreviations. CR, complete response; VOD/SOS, veno-occlusive disease/sinusoidal obstructive syndrome.

Sensitivity analysis

Both deterministic and probabilistic sensitivity analyses were performed in order to assess the uncertainty of the variables used in the model and determine the robustness of the results.

In the scenario analyses, alternatives to the base-case analysis were proposed. Modified variables included time horizon (70, 50, 30, or 10 years vs a lifetime horizon), pharmacologic costs (considering vial wastage vs vial sharing), extrapolation of KM data for OS (exponential [HR from the last observation; HR = −0.0075 for defibrotide and HR = −0.0147 for controls] vs the semiparametric approach), long-term survival adjustment (no adjustment or adjustment per Goldman et al. [HR = 2.5; 95% CI = 1.3–3.7]²⁸ vs Nivison-Smith et al.²⁴) and utilities (constant over time vs decreasing with age).

In addition, a one-way sensitivity analysis was performed, in which some variables were individually modified to minimum or maximum values (Table 3). Minimum and maximum values were obtained based on standard deviation (SD) or standard error (SE) and, in cases where SD/SE was not available, a variation of ±20% (in unit costs) was applied or extreme ranges were assumed, as in the cost per day of extended LoS due to severe VOD/SOS (100% ICU cost and 100% transplant unit cost).

Table 3. Univariate sensitivity analysis parameters.

	Minimum value	Base case	Maximum value
Discount rate for effects, %	0	3	5
Extended stay due to severe VOD/SOS, days
Defibrotide + BSC	0	7.48	28.11
BSC alone	0	23.18	55.69
Cost per extra day of stay, €
Defibrotide + BSC	909.78	1,013.23	1,254.61
BSC alone	909.78	1,116.68	1,254.61
Average duration of treatment with defibrotide, days	14.8	17.5	20.4
Average weight, kg	47.4	53.7	60.4
Average daily dose defibrotide, mg/kg/day	23.36	25.00	26.69
Proportion in CR at day 100, %
Defibrotide arm in phase 3 study	15.3	23.5	31.8
Historical control arm in phase 3 study	0.0	9.4	19.5
Utility in ‘severe VOD/SOS’ health state	0.166	0.208	0.250

Abbreviations. VOD/SOS, veno-occlusive disease/sinusoidal obstruction syndrome; BSC, best supportive care; CR, complete response.

In the probabilistic sensitivity analysis, 1,000 simulations were carried out using the Monte Carlo method and were found to be consistent with the recommendations of the literature²⁹. Costs were assumed to follow a generalized gamma distribution and, for the parameters related to patients or treatment, a normal distribution was selected. For utilities and for variables with probabilities, a beta distribution was used since these were limited to a range of 0–1.

Results

Base case

The results of the cost-effectiveness analysis for the base case are shown in Table 4. The deterministic results of the base case show that the use of defibrotide provided more life-years (LYs) and quality-adjusted LYs (QALYs) than BSC alone (+1.348 LYs and +1.214 QALYs for a lifetime horizon) at a higher cost (+€33,708 for a lifetime horizon). The ICER and ICUR were both <€30,000 per LY and per QALY, the efficiency threshold commonly accepted in Spain^30,31.

Table 4. Results of the base case.

	Defibrotide + BSC	BSC alone	Defibrotide + BSC vs BSC alone
Total costs, €	58,409	24,701	+33,708
Pharmacologic cost	50,352	0	+50,352
Hospital stay cost	8,057	24,701	−16,644
LYs	5.354	4.006	+1.348
QALYs	4.655	3.440	+1.214
ICER (€/LY)			25,007
ICUR (€/QALY)			27,757

Abbreviations. BSC, best supportive care; LY, life-year; QALY, quality-adjusted life-year; ICER, incremental cost-effectiveness ratio; ICUR, incremental cost-utility ratio.

Sensitivity analyses

Deterministic sensitivity analysis

Table 5 shows the results of the scenario analysis, including the ICER and ICUR resulting from the comparison of defibrotide vs BSC alone. The cost-effectiveness threshold of €30,000/QALY was not exceeded in any of these scenarios. The results of the one-way sensitivity analysis are represented by a tornado diagram, showing the impact of the minimum and maximum values of each variable on the ICUR of the base case (Figure 3). Variation on the extended hospital stay showed the greatest impact on the results of the base case.

Figure 3. Results of the univariate analysis: tornado diagram. Abbreviations. VOD/SOS, veno-occlusive disease/sinusoidal obstruction syndrome; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Table 5. Results of deterministic analysis.

Parameter	Scenario	ICER vs BSC, €/LY	ICUR vs BSC, €/QALY
Base case		25,007	27,757
Temporal horizon
Pharmacologic cost	Wastage	€26,606	€2,532
KM data extrapolation	Exponential, HR from last observation	€24,701	€2,166
Long-term survival adjustment	No adjustment	€24,927	€27,669
	Goldman et al.^28	€24,947	€27,692
Utilities	Constants over time	€25,007	€26,516

Abbreviations. ICER, incremental cost-effectiveness ratio; BSC, best supportive care; LY, life-years; QALY, quality-adjusted life-year; ICUR, incremental cost-utility ratio; KM, Kaplan-Meier; HR, hazard ratio.

Probabilistic sensitivity analysis

The mean ICER (expressed in QALYs) obtained from 1,000 simulations was 1.215 (95% CI = 1.180–1.252), and the mean incremental cost was €33,821 (95% CI = €16,845–€49,553). The resultant mean ICUR was €27,829/QALY, which was in line with the base-case results.

Figure 4 shows the incremental results of defibrotide vs BSC alone using a cost-effectiveness plane; 61.9% of the simulations fell under the willingness-to-pay threshold of €30,000/QALY³². All simulations were located in the first quadrant, representing the higher cost and greater efficiency for defibrotide.

Figure 4. Probabilistic sensitivity analysis results. Incremental cost-effectiveness plan. Abbreviations. WTP, willingness-to-pay; QALY, quality-adjusted life-year.

Discussion

Given the poor outcome associated with severe VOD/SOS, the survival benefit provided by defibrotide treatment for VOD/SOS patients fills a significant need for the treatment of this rare but frequently fatal complication in patients who receive HCT¹⁴. For this reason, it is important to analyze the cost-effectiveness of defibrotide for the treatment of severe VOD/SOS.

The results of this analysis demonstrate that defibrotide treatment in patients who develop severe VOD/SOS after HCT is a cost-effective option vs BSC alone. The higher cost associated with defibrotide (+€33,708) occurred exclusively at the beginning of the acute phase and, as demonstrated by the results of the model, the long-term benefits (+1.348 LYs and +1.214 QALYs) offset the incremental costs. The cost-effectiveness ratios obtained were below the cost-effectiveness threshold of €30,000/QALY commonly used in Spain³². It should also be noted that the cost of defibrotide therapy, relative to the overall costs of transplantation and of managing HCT patients, especially those with post-HCT complications³³, is low. Indeed, it has been estimated that post-HCT VOD/SOS can increase hospital and ICU costs by up to 3-fold³⁴.

The economic evaluations of defibrotide published in Spain are sparse. In Spain, in a retrospective cohort study of adults diagnosed with VOD/SOS after HCT, the cost-effectiveness of defibrotide was calculated using the median treatment-related cost and the median OS, without any long-term modeling techniques. The median-based cost-effectiveness ratio was €800/life-day gained³⁵. Based on a retrospective hospital database analysis, Veenstra et al.³⁶ estimated the budget impact and cost-effectiveness of introducing defibrotide to a transplant center in the US. The reported ICER was $47,736/QALY gained, with an 88% probability of defibrotide being cost-effective at a $100,000/QALY threshold. In summary, this analysis, which uses a Markov model, based, in part, on prospective data and which considered long-term effects to determine the cost-effectiveness of defibrotide for the treatment of severe VOD/SOS post-HCT in Spain, appears to be unique.

In this study, the main efficacy variables were obtained from the phase 3 study¹⁴. Consistent with previous clinical studies of defibrotide, the efficacy endpoints evaluated in the phase 3 study demonstrated that defibrotide use in patients with severe VOD/SOS and MOD post-HCT was associated with a clinically significant improvement in day 100 survival and CR rates^14,37.

It should be noted that there were some limitations inherent to the design of the phase 3 study. While patients in the defibrotide treatment arm were enrolled prospectively, the historical controls were selected by an independent, blinded medical review committee through a retrospective review of patient records¹⁴. Although use of a historical control group provides a feasible mechanism for comparison when a randomized controlled group is not possible for ethical issues, the different methodologies for identifying patients is a potential source of variation between the treatment groups, and the number of patients in the historical control group was small. Since data from the phase 3 study were used to build the model presented here, these limitations should be considered when evaluating this cost-effectiveness model. However, it should be noted that, in the case of the phase 3 data, the records for the historical control group were screened from the same medical centers that enrolled the defibrotide-treated group, with minimal temporal disparity between the historical and treatment populations, in order to limit potential variation.

It should be emphasized that the cost of defibrotide could be affected by a number of variables, including mean treatment length, average body weight, and vial wastage. Furthermore, based on guidance from a panel of experts, this study assumed a treatment duration that was shorter (17.5 [range = 14–21] days) than the median of 21.5 (range = 1–58) days observed in the phase 3 study or the 21-day duration of therapy recommended in the summary of product characteristics^13,14.

Finally, the sensitivity analysis showed that the results of the base case were robust because the cost-effectiveness threshold of €30,000/QALY was not exceeded in any of the given scenarios, showing that defibrotide is a cost-effective alternative in patients experiencing severe VOD/SOS when compared with BSC alone^30–32.

Conclusions

In brief, this economic analysis demonstrated that defibrotide therapy provides a substantial QALYs gained for patients with severe VOD/SOS (defined as VOD/SOS with MOD), making defibrotide a cost-effective treatment in this setting despite its higher cost in the acute phase.

Transparency

Declaration of funding

This study was supported by Jazz Pharmaceuticals.

Declaration of financial/other interests

DCR and AV are employees of Hygeia Consulting SL; Hygeia received funding from Jazz Pharmaceuticals to conduct this analysis. ACR has served in an advisory role for Jazz Pharmaceuticals. MGV has consulted for Jazz Pharmaceuticals. GGG has received grants from Jazz Pharmaceuticals, Pfizer, and Gilead. MCH is an employee of and holds stock ownership and/or stock options in Jazz Pharmaceuticals. TAU, EGT, and ARG have no conflicts to disclose.

JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Previous presentations

These data were previously presented, in part, at the 46th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), held virtually from 29 August to 1 September 2020.

Acknowledgements

Medical writing and editorial assistance were provided by Erica Chevalier-Larsen, PhD, CMPP, of SciFluent Communications, Inc., and were financially supported by Jazz Pharmaceuticals.

Data availability statement

Data that support the findings of this study are openly available in Ministerio de Sanidad, Consumo y Bienestar Social - Portal Estadístico del SNS - Registro de Altas de los Hospitales Generales del Sistema Nacional de Salud at https://www.mscbs.gob.es/estadEstudios/estadisticas/cmbd.htm and from the literature cited in References. Additional data that support the findings of this study are available from the corresponding author, DCR, upon reasonable request.