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Abstract

Background

In clinical practice, treatment sequences of biologicals are applied for active fistulising Crohn’s disease, however underlying health economic analyses are lacking.

Objective

The purpose of this study was to analyse the cost-effectiveness of different biological sequences including infliximab, biosimilar-infliximab, adalimumab and vedolizumab in nine European countries.

Methods

A Markov model was developed to compare treatment sequences of one, two and three biologicals from the payer’s perspective on a five-year time horizon. Data on effectiveness and health state utilities were obtained from the literature. Country-specific costs were considered. Calculations were performed with both official list prices and estimated real prices of biologicals.

Results

Biosimilar-infliximab is the most cost-effective treatment against standard care across the countries (with list prices: €34684–€72551/quality adjusted life year; with estimated real prices: €24364–€56086/quality adjusted life year). The most cost-effective two-agent sequence, except for Germany, is the biosimilar-infliximab–adalimumab therapy compared with single biosimilar-infliximab (with list prices: €58533–€133831/quality adjusted life year; with estimated prices: €45513–€105875/quality adjusted life year). The cost-effectiveness of the biosimilar-infliximab–adalimumab–vedolizumab three-agent sequence compared wit biosimilar-infliximab –adalimumab is €87214–€152901/quality adjusted life year.

Conclusions

The suggested first-choice biological treatment is biosimilar-infliximab. In case of treatment failure, switching to adalimumab then to vedolizumab provides meaningful additional health gains but at increased costs. Inter-country differences in cost-effectiveness are remarkable due to significant differences in costs.

Keywords

Cost-effectiveness biosimilar-infliximab infliximab adalimumab vedolizumab biosimilar fistulising Crohn’s disease

Key summary

In clinical practice, treatment sequences of biologicals are applied for active fistulising Crohn's disease, however underlying health economic analyses are lacking.

The suggested first-choice biological treatment is bsIFX. In case of treatment failure, switching to adalimumab then to vedolizumab provides meaningful additional health gains but at increased costs.

Introduction

Fistulising Crohn’s disease (CD) can lead to significant impairment in health-related quality of life and imposes substantial burden both on patients and society.^1,2 Fistulas are often difficult to treat and result in significant costs through the use of medication, surgical intervention and the need for hospitalisation.³ Biological drugs has dramatically changed the treatment of CD. Randomised controlled trials (RCTs) established the clinical efficacy and safety of infliximab (IFX) for the treatment of fisultising CD, using fistula closure as primary endpoint.^4,5 The scientific evidence for adalimumab (ADA) and vedolizumab (VEDO) is weaker as their effects were examined in subgroups of patients with fistulising CD in RCTs but only as secondary endpoints.^6–11 IFX is the only biological drug that is specifically indicated for the treatment of adults with fistulising CD, but in clinical practice ADA and VEDO are also used to treat fistulising CD.^12–15 Access to biologicals varies significantly between countries largely driven by budgetary constraints.^16,17 Biological therapy and hospitalisation are the main cost drivers in CD, although studies focusing specifically on fistulising CD are scarce.^1,2,18,19

Biosimilars, due to their lower price, have the potential to improve access to treatment and achieving substantial savings relative to the reference medical products. The first biosimilar monoclonal antibody, biosimilar-infliximab (bsIFX) was approved by the European Medicines Agency (EMA) in 2013 and U.S. Food and Drug Administration (FDA) in 2016 for the same indications as the originator molecule.²⁰ Although bsIFX is already used in many countries, few studies have dealt with its health economic aspects. Budget impact analyses suggest that significant savings can be achieved with bsIFX in CD.^21,22

Three cost-utility studies of biological treatment in fistulising CD assessed the cost-effectiveness of IFX therapy in comparison with standard care from the third-party payers’ perspective.^23–25 According to our knowledge, no health economic analyses with ADA, VEDO and bsIFX have been published yet. Inter-country comparisons are also lacking in the literature. More importantly, there is no cost-effectiveness evidence on the sequential use of biological treatment in fistulising CD. Health gains and costs of these treatment sequences have to be analysed and compared to identify the most cost-effective treatment strategy, particularly since the advent of including biosimilars.

The aim of our study was to analyse the cost-effectiveness of the different treatment sequences with available biologicals (IFX, bsIFX, ADA, VEDO), for the treatment of fistulising CD in nine European countries, namely in Belgium, France, Germany, Hungary, Italy, Spain, Sweden, the Netherlands and the UK.

Materials and methods

Model overview

A Markov model was developed to analyse the cost-effectiveness of treatment sequences including bsIFX for the treatment of patients with active fistulising CD (Figure 1). Model states are described by the health states and the therapies (Table 1). Health states were defined by fistula healing related primary and secondary endpoints from RCTs.
Figure 1.
The structure of the Markov model for fistulising Crohn’s disease (CD).

Table 1.
Model states: health states, therapies applied and utilities.

Model states Health state Therapy Utility^a

‘A’ Initiation of Biologic Therapy State H1: Patients with draining fistula(s) with failure to adequate previous conventional treatment or previous biological treatment T1: induction therapy with biological treatment^b 0.40

‘B’ Complete fistula healing state^c H2: patients without any fistula T2: ongoing maintenance biological treatment

or 0.83

T3: non-biological standard therapy

‘C’ Incomplete fistula healing state^d H3: incomplete fistula healing, patients with at least 50% reduction in number of fistulas T2: ongoing maintenance biological treatment

or 0.68

T3: non-biological standard therapy

‘D’ Biologic therapy refractory state H1: Patients with draining fistula(s) with failure to adequate previous treatment T3: non-biological standard therapy 0.40

‘E’ Surgery state H1: Patients with draining fistula(s) with failure to adequate previous treatment T4: major fistula surgery 0.40

‘F’ Post surgery remission state H2: patients without any fistula T3: non-biological standard therapy 0.83

‘G’ Death H4: death – –

a
Utility weights are based on Linsay et al., 2008.^25,35

b
30% of the patients have minor fistula surgery.

c
Secondary end-point in the randomised controlled trial of infliximab by Present et al.,1999⁴ and in the following studies with subgroup of fistulising CD patients: Hanauer et al., 2006 (CLASSIC I)⁶ induction adalimumab study, Sandborn et al., 2007 (GAIN)⁷ induction adalimumab study. Primary end-point in Sands et al., 2004 (ACCENT II)⁵ maintenance infliximab study and secondary end-point in in the following studies with subgroup of fistulising CD patients: Colombel et al., 2009 (CHARM)⁸ adalimumab maintenance study, Sandborn et al., 2013 (GEMINI)⁹ maintenance study.

d
Primary end-point in the randomised controlled trial of infliximab in Present et al., 1999⁴ and secondary end-point in in the following studies with subgroup of fistulising CD patients Hanauer et al., 2006 (CLASSIC I)⁶ induction adalimumab study, Sandborn et al., 2007 (GAIN)⁷ induction adalimumab study.

The model focuses solely on fistulising CD and does not take account of treatment effects on luminal CD symptoms (e.g. improvement of Crohn’s Disease Activity Index (CDAI) score).

At the end of each subsequent model cycle, patients either remained in the same model state or moved to a different one. The model runs in three-month cycles representing the course of the disease by time and the time horizon is five years. Patients could make transitions between model states at the end of a cycle. These movements are represented by the arrows on Figure 1.

In the cost-effectiveness model, first we compared single biological drug treatment with standard (non-biological) care. Then different treatment sequences of multiple biologicals were compared with each other. If more than one biological was included in a treatment sequence, it was assumed that all patients who get to the model state ‘D’ would immediately start with the subsequent biological therapy and moved to model state ‘A’. Once the patients went through all available biologicals, biological treatment could not be restarted again and they continued with non-biological standard care in the model state ‘D’ or moved to model state ‘E’. Patients receiving non-biological standard care could move from model state ‘D’ to model states ‘A’ or ‘C’, but this was allowed only once during the time horizon of the model. From model state ‘D’ patients could move to model state ‘E’. Patients with successful major fistula surgery moved to model state ‘F’. Patients with unsuccessful first surgery went through a second procedure, however a maximum of two major fistula surgeries was allowed during the time horizon of the model. Combining fistula surgery with biological treatment can have beneficial effects however, not all patients have surgery alongside the initiation of biological drug treatment.^26–28 Hence, the model linked minor fistula surgery to the ‘Initiation of biologic treatment’ model state but assumed that this type of intervention applied to only 30% of the patient population.

Patients

The cost-effectiveness model was populated with patients with fistulising active CD who (a) had single or multiple draining abdominal and/or perianal fistulas at baseline; (b) who had not responded to conventional treatment (including antibiotics, drainage and immunosuppressive therapy); and (c) were eligible for biological treatment. These inclusion criteria correspond with the inclusion criteria of the only RCT designed specifically for fistulising CD,⁴ with the fistulising subgroups of other RCTs in CD, as well as with the drug indications.^5,8,9 We assumed that the average age of the patients was 40 years and the average weight was 65 kg (standard deviation (SD) = 16).²⁹ These figures are in line with the baseline characteristics of patients in the Present et al. study of 1999,⁴ and other fistulising subgroups in RCTs.^5,8,9

Comparison of treatment sequences

In the cost-effectiveness model we compared different treatment sequences including the available biologicals as well as non-biological standard care. Each treatment sequence could include a maximum of three different biologicals: IFX, bsIFX, ADA and VEDO followed by standard care. Each biological could appear only once in the treatment sequence. First, we calculated the cost-effectiveness of each biological drug (IFX, bsIFX, ADA and VEDO) followed by standard care compared with non-biological standard care. In the second step, we took the most cost-effective single biological and analysed the cost-effectiveness of adding a second biological to the sequence. In the third step, the most cost-effective two-item sequence was chosen and we explored the cost-effectiveness of adding a third biological.

Transition probabilities

Clinical efficacy data were derived from RCTs and were used to calculate transition probabilities. In the RCTs, fistulising CD-related inclusion criteria were typically the presence of single or multiple draining abdominal or perianal fistulas of at least three months’ duration as a complication of CD, concurrent therapies for CD in stable doses were permitted and patients were excluded from the study if they had a stricture or abscess for which surgery might be indicated. In RCTs where fistulising patients were only a subgroup of the sample, moderate or severe active CD (as measured by the CDAI score) was a criterion of inclusion. Patients were biological naive in some RCTs^4,5 and have already had previous exposure to anti-tumour Necrosis Factor Alpha (anti-TNF-alpha) treatment in others.^8,9,30

Table 2 shows the transition probabilities of movements between model states. Transition probabilities were calculated based on efficacy data from RCTs and cohorts,^{4,5,8,9,26,31–33} and some estimations had to be applied due to lack of epidemiological data in fistulising CD. We used country-based mortality data of the general population and a higher mortality rate was considered for ‘C’, ‘D’ and ‘E’ model states (Table 2).³⁴
Table 2.
Transition probabilities between model states.

Item Substance Source (references) Probability projected for model cycles (3 months) Risk of bias (reason)

Probability of complete healing Infliximab Present 1999 5 mg infliximab branch week 18 Projection for week 12⁴ 41.1% Low (primary endpoint)

Adalimumab Colombel et al., 2009, (Patients with healed fistulas adalimumab every other week (eow) and weekly combined arm 16^th week 36% 20^th week 34% → estimation for 18^th week: 35%) Projection for week 12⁸ 25.0% Medium (subgroup analysis, secondary endpoint)

Vedolizumab Feagan et al., 2015 Number of patients with fistula closure at 14^th week Table (arm: vedolizumab every 8 weeks): 29,4% Projection for week 12³⁰ 25.8% Medium (subgroup analysis, secondary endpoint)

Placebo Present et al., 1999 placebo branch⁴ 8.8% Low (primary endpoint)

Probability of incomplete healing Infliximab Present et al., 1999 5 mg infliximab branch⁴ 8.8% Low (primary endpoint)

Adalimumab Estimation based on: Present et al., 1999 and Colombel et al., 2009 (infliximab incomplete healing/complete healing x adalimumab complete healing)^4,8 5.3% High (estimation, projection from maintenance data, subgroup analysis, secondary endpoint)

Vedolizumab Estimation based on: Present et al., 1999 and Sandborn et al., 2013 (infliximab incomplete healing/complete healing x vedolizumab complete healing)^4,9 5.5% High (estimation, projection from maintenance data, subgroup analysis, secondary endpoint)

Placebo Present 1999 placebo branch⁴ 8.8% Low

Probability of relapse Infliximab Sands 2004 infliximab branch (ACCENT II.)⁵ 17.6% Low

Adalimumab Estimation: Sands et al., 2004 (efficacy of placebo) and Colombel et al., 2009^5,8 (relative efficacy of adalimumab compared to placebo) 20.1% Medium (estimation, subgroup analysis, secondary endpoint)

Vedolizumab Estimation: Sands et al., 2004 (efficacy of placebo) and Sandborn et al., 2013 (relative efficacy of vedolizumab compared to placebo)^5,9 16.3% Medium (estimation, subgroup analysis, secondary endpoint)

Placebo Sands et al., 2004 placebo branch⁵ 30.7% Low

Probability moving from complete healing to incomplete healing Infliximab Calculated based on Sands et al., 2004 (Accent II.)⁵ 2.6% Low

Adalimumab Estimation based on Sands et al., 2004 and Colombel et al., 2009: infliximab complete healing to incomplete healing/infliximab_relapse x adalimumab_relapse^5,8 2.8% High (subgroup analysis, secondary endpoint)

Vedolizumab Estimation based on Sands 2004 and Sandborn 2013: infliximab complete healing to incomplete healing/infliximab_relapse x vedolizumab_relapse^5,9 2.4% High (subgroup analysis, secondary endpoint)

Placebo Calculated based on Sands et al., 2004 (Accent II.)⁵ 1.0% Low

Probability of surgery – Based on three Cohort studies (Amiot et al., 2014, Molendijk et al., 2014, Pittet et al., 2010)^31–33 15.9% Low

Probability of surgical remission – Based on Yassin et al., 2014 meta-analysis of cohort studies²⁶ 10.6% Low

Other assumptions: Mortality: we assume different mortality rates for complete healing (OR = 1) and incomplete healing (OR = 1.266) and refracter (OR = 2.256) health states (based on: Lichtenstein et al. 2006).³⁴ The source of Life Tables: EUROSTAT. Due to the lack of data we assume that the probability of moving from ‘Incomplete healing’ to ‘Complete healing’ model state is 0. Due to the lack of data for fistulising patients, we assume that the efficacy of the 2nd and 3rd biological treatment will decrease by 10% (regardless of the agent).

Costs and outcomes

The analyses were performed from the third-party payer perspective. IFX has patient weight-dependent dosing, the remaining portion of drug in the vial is either used (no wasting) or not (wasting) for the treatment of another patient. In the base case we considered no wasting for IFX and for bsIFX. Country-specific unit costs were considered based on official price lists and available sources to calculate health care utilisation costs.

At first we used the official list prices of biologicals (see Table 3). List prices represent the maximum prices, real prices are lower but not publicly available. Thus, we repeated the calculations using a 30% price decrease for bsIFX and IFX, and a 20% decrease for ADA (as biosimilar-ADA is not yet available, a lower real price reduction is assumed for ADA). VEDO was registered for CD in 2014, therefore we assumed no decrease in prices.
Table 3.
Input data for the model: costs (€, 2015).

Item Country Biosimilar- infliximab 1 × 100 mg Originator- infliximab 1 × 100 mg Adalimumab 2 × 40 mg Vedolizumab 1 × 300 mg

Belgium €388.87 €388.87 €950.64 €2264.10

France €434.403 €434.403 €859.38 UK price

Germany €701.86 €933.67 €1843.77 €2987.97

Hungary €345.50 €492.14 €881.70 UK Price: €2887.32

Italy €428.01 €570.68 €1068.56 €2256

Netherlands €573.99 €573.99 €1144.90 €2235.54

Spain €510.29 €615.88 €1127.57 €3662.79

Sweden €450.29 €552.81 €1087.15 €2374.01

UK €531.92 €591.01 €991.94 €2887.32

Conversions: Hungary €1 = 312 HUF; Sweden: €1 = 9.3 SEK; UK: €1 = £0.71.

Sources of biological drug costs:

Belgium: Rijksinstituut voor ziekte-en invaliditeitsverzekering. Pharmaceutical list prices (2016), (last accessed 18/05/2016).

France, https://www.vidal.fr (last accessed 18/05/2016).

Germany: Medipreis. Preisvergleich für Medikamente (2016), https://www.medipreis.de (last accessed 18/05/2016).

Hungary: National Health Insurance Fund Administration brutto price Országos Egészségbiztosítási Pénztár Publikus Gyógyszertörzs (1 June 2016). (last accessed 18/05/2016).

Italy: Medicina e Società (2016), http://www.medisoc.it/scheda-tecnica-infliximab/ (last accessed: 18/05/2016).

Netherlands: Medicijnkosten, http://www.medicijnkosten.nl (last accessed 18/05/2016).

Spain: http://a.nomenclator.org (last accessed 19/05/2016).

Sweden: Dental and Pharmaceutical Benefits Agency (TLV), http://www.tlv.se/In-English/medicines-new/ (last accessed 18/05/2016).

UK: British National Formulary (BNF), https://www.evidence.nhs.uk/ (last accessed 18/05/2016).

Administration costs for biologicals were considered only for infusions (bsIFX, IFX, VEDO) as the administration cost of subcutaneous injections (ADA) is usually minor. For standard care we considered the cost of sulfasalazine, 2000 mg/day and 20 mg prednisolone/day. In this patient population other per os drugs are also used such as azathioprine and/or antibiotics, which would result in similar costs. Both the items considered for the monitoring of patients and their frequency varied according to the treatments applied and also across countries. Monitoring included routine laboratory tests (blood cell count, liver and kidney function test, albumin, iron, ferritin, C-reactive protein, urine analysis, faecal calprotectin test, outpatient visit, chest x-ray, abdominal ultrasound, magnetic resonance and endoscopy (rectosigmoidoscopy and colonoscopy). Non-surgical hospitalisation and costs were considered only for 40% of patients in model state ‘D’. Informal care and transportation costs were not included.

Utility values were attached to each model state to calculate quality adjusted life years (QALYs) in cost-effectiveness analyses. Few data are available on the utility of health states of patients with fistulising CD.^25,35 We applied utility weights presented by Lindsay at al. in 2008²⁵ (Table 1). Discounted costs and outcomes were calculated on a five-year time horizon.

Sensitivity analyses

The structural uncertainty of the model was evaluated using one-way sensitivity analysis varying parameters such as price, time horizon, patients’ age and weight, health state utilities, cost of surgery and inpatient care, discounting rates and wasting of remaining drugs in the vial. Productivity loss was not included in the base case analysis but was considered in the sensitivity analysis providing an assessment from the societal perspective. A temporary productivity loss of 20-day sick leave per year (multiplied by average gross daily wages of the countries) was considered for ‘A’, ‘D’ and ‘E’ model states. Parameter uncertainty (transitional probabilities, costs, utility weights, patients’ characteristics) was evaluated using probabilistic sensitivity analysis.

Results

Cost-effectiveness analyses (base case)

Incremental costs, QALY gains and the incremental cost-effectiveness ratios (ICERs) are presented in Table 4 by countries.
Table 4.
Cost-effectiveness results (third-party payer’s perspective, time horizon of five years, patients mean weight 65 kg, no wasting of remaining infliximab in the vial, utility weights from Lindsay et al.,²⁵ results shown in €).

Belgium France Germany Hungary Italy Netherlands Spain Sweden UK

St. care

QALY 2.097 2.027 2.031 1.990 2.033 2.100 2.031 2.034 2.007

Cost 12,250 11,786 15,956 3595 15,047 13,717 18,272 33,178 20,273

One biological vs st. care

bsIFX vs st. care

Δ QALY to st. care 0.2524 0.2462 0.2461 0.2436 0.2460 0.2523 0.2461 0.2460 0.2442

Δ cost to st. care 9697 10,764 17,854 8450 10,840 14,910 13,394 17,095 15,603

ICER to st. care 38,420 43,721 72,551 34,684 44,059 59,101 54,427 69,491 63,908

IFX vs st. care

Δ QALY to st. care 0.252 0.246 0.246 0.244 0.246 0.252 0.246 0.246 0.244

Δ cost to st. care 9697 10,764 23,512 12,007 14,322 14,910 15,971 19,597 17,040

ICER to st. care 38,420 43,721 95,540 49,286 58,215 59,101 64,898 79,663 69,793

ADA vs st.care

Δ QALY to st. care 0.136 0.132 0.132 0.131 0.132 0.136 0.132 0.132 0.131

Δ cost to st. care 9091 8151 17,480 7941 10,361 11,411 11,417 14,157 9989

ICER to st. care 66,921 61,562 132,071 60,646 78,296 84,031 86,263 106,990 76,099

VEDO vs st.care

Δ QALY to st. care 0.168 0.164 0.164 0.162 0.164 0.168 0.164 0.164 0.162

Δ cost to st. care 14,117 17,799 18,964 17,504 14,307 14,598 23,295 20,228 20,163

ICER to st. care 83,806 108,561 115,696 108,026 87,299 86,688 142,118 123,437 124,090

Two biologicals vs biosimilar IFX

bsIFX−ADA vs bsIFX

Δ QALY to bsIFX 0.108 0.105 0.105 0.103 0.105 0.108 0.105 0.105 0.104

Δ cost to bsIFX 6963 6129 14,016 6857 7723 8370 8176 8146 6367

ICER to bsIFX 64,223 58,533 133,831 66,589 73,730 77,183 78,068 77,765 61,500

bsIFX−VEDO vs bsIFX

Δ QALY to bsIFX 0.133 0.128 0.128 0.126 0.128 0.133 0.128 0.128 0.127

Δ cost to bsIFX 11,411 14,677 15,285 15,289 11,207 11,157 18,700 13,507 15,374

ICER to bsIFX 85,734 114,294 118,993 121,094 87,231 83,808 145,582 105,126 121,121

Three biologicals vs bsIFX−ADA

bsIFX−ADA−VEDO vs bsIFX−ADA

Δ QALY to bsIFX−ADA 0.120 0.115 0.115 0.113 0.115 0.120 0.115 0.115 0.113

Δ cost to bsIFX−ADA 10,745 13,795 14,361 14,395 10,533 10,444 17,587 12,652 14,434

ICER to bsIFX−ADA 89,775 120,003 124,858 127,732 91,537 87,214 152,901 109,945 127,207

ADA: adalimumab; bsIFX: biosimilar-infliximab; ICER: incremental cost-utility ratio; IFX: originator-infliximab; QALY: quality adjusted life year; st. care: standard care; VEDO: vedolizumab.

Discount rates: equal discount rates were applied for both costs and effects in the following countries: France, Germany, Italy, Spain, Sweden 3.0%, Hungary 3.7%, UK 3.5%. For Belgium costs were discounted by 3% and effects by 1.5%, and for the Netherlands by 4.0% and 1.5%, respectively.

Single biologicals compared with standard care – list price

Given the same clinical efficacy and safety for IFX and bsIFX, additional QALY gains compared with standard care were equal and varied between 0.244–0.252 QALY across countries due to differences in mortality and discount rates. Lower additional QALY gains were observed for ADA and VEDO in all the nine countries, 0.113–0.136 and 0.162–0.168 QALY, respectively. In six countries where the list prices of bsIFX were lower than of IFX (Germany, Hungary, Italy, Spain, Sweden and the UK), the additional costs compared with standard care were lower for bsIFX (varied between €8450–€17854) than for IFX (varied between €9697–€23512), and the highest were for VEDO (varied between €14117–€23295). Germany, Italy and the Netherlands are exceptions where the additional cost of the VEDO scenario was slightly lower than IFX (Table 4). The additional cost of ADA compared with standard care varied between €7941–€17480. The ICER (compared with standard care) was the lowest for bsIFX in all the nine countries and varied between €34684–€72551/QALY. Due to the same list prices of bsIFX and IFX, the ICERs of these two drugs were identical in Belgium, France and the Netherlands. The ICERs were between €38420–€95540/QALY for IFX, €60646–€132071/QALY for ADA, and €83806–€142118/QALY for VEDO (Table 4).

Treatment sequences with two or three biologicals – list prices

Since bsIFX was the most cost-effective treatment as a one-agent treatment sequence, this was chosen as a comparator for treatment sequences with two and three biologicals. Adding a second biological to the treatment sequence after bsIFX provided additional QALY gains (0.103–0.133) compared with bsIFX alone but at larger additional costs (€6129–€18700). The bsIFX−ADA was the most cost-effective two-agent treatment sequence in all countries with ICERs (compared with bsIFX) between €58533–€133831/QALY. Germany was an exception where the bsIFX–VEDO sequence resulted in a lower ICER than the bsIFX–ADA sequence. The ICERs of the bsIFX–VEDO treatment sequence were between €83808–€145582/QALY (Table 4). Adding a third biological (VEDO) to the two-agent treatment sequence provided additional QALY gains (compared with bsIFX–ADA sequence: 0.113–0.120) but at larger additional costs (€10444–€17587). The ICERs varied between €87214–€152901/QALY. In Germany, adding ADA after bsIFX–VEDO sequence resulted in an ICER of 140666/QALY compared with bsIFX–VEDO.

Cost-effectiveness with estimated real prices

We repeated the calculations applying 30% decrease in the list price of IFX and bsIFX, and 20% for ADA in each country. This resulted in a 19–30% decrease of the ICERs for bsIFX compared with standard care (€24364–€56086/QALY), a 21–30% decrease for IFX (€27141–€67762), and a 14–20% decrease for ADA (€48713–€107255). The ICER of the bsIFX–ADA treatment sequence (compared with bsIFX) decreased by 20–22% (€45513–€105875/QALY). Applying these estimated real prices resulted in the bsIFX−ADA sequence becoming the most beneficial among the two-agent sequences, also in Germany (results are presented in Table 5).
Table 5.
Cost-effectiveness results with price discounts of 30% for originator and biosimilar-infliximab (bsIFX) and 20% for adalimumab (ADA) (third-party payer’s perspective, time horizon five years, patients mean weight 65 kg, no wasting of remaining infliximab (IFX) in the vial, utility weights from Lindsay et al.,²⁵ results shown in €).

Belgium France Germany Hungary Italy Netherlands Spain Sweden UK

One biological vs st. care

bsIFX vs st. care

Δ cost to st. care 6850 7584 12,716 5936 7705 10,737 9658 13,797 11,724

ICER to st. care 27,141 30,807 51,670 24,364 31,319 42,558 39,245 56,086 48,017

IFX vs st. care

Δ cost to st. care 6850 7584 16,676 8426 10,143 10,737 11,462 15,549 12,729

ICER to st. care 27,141 30,807 67,762 34,585 41,228 42,558 46,575 63,206 52,137

ADA vs st.care

Δ cost to st. care 7398 6621 14,196 6378 8457 9383 9409 12,220 8228

ICER to st. care 54,459 50,005 107,255 48,713 63,912 69,100 71,091 92,354 62,683

Two consecutive biologicals vs bsIFX

bsIFX−ADA vs bsIFX

Δ cost to bsIFX 5455 4765 11,088 5473 6026 6576 6386 6419 4803

ICER to bsIFX 50,309 45,513 105,875 53,151 57,529 60,634 60,977 61,281 46,395

ADA: adalimumab; bsIFX: biosimilar-infliximab; ICER: incremental cost-utility ratio; IFX: originator-infliximab; QALY: quality adjusted life year; st.care: standard care; VEDO: vedolizumab.

Quality adjusted life year (QALY) gains are equal to results presented in Table 4 as only drug costs were modified. Vedolizumab price was not discounted hence no change in the vedolizumab versus standard care and the bsIFX-VEDO vs bsIFX scenario.

One-way sensitivity analysis

One-way sensitivity analyses results for bsIFX compared with standard care are presented in Table 6. The effects were comparable for other treatment sequences as well. Taking into account productivity loss, ICERs decreased by 6–27%. Also, a 10% increase in utility weights decreased the ICERs by 9%, and a 10% decrease increased the ICERs by 11%. On a 10-year time horizon ICERs decreased by 5–6%. The results were the least sensitive to discounting (−5 to −1%), to the 10% change in the hospitalisation (surgery, inpatient stay) costs (−0.3% to +0.3%) and to the ±5 year change in the age of patients (–0.5% to +0.3%).
Table 6.
One-way sensitivity analysis for biosimilar-infliximab (bsIFX) – vs standard care.

Base case estimate Sensitivity estimate Belgium France Germany Hungary Italy Netherlands Spain Sweden UK

Base case 38,420 43,721 72,551 34,684 44,059 59,101 54,427 69,491 63,908

Body weight 65 kg 60 kg −8% −8% −7% −8% −7% −7% −7% −5% −6%

70 kg 8% 8% 7% 8% 7% 7% 7% 5% 6%

Time horizon 5 years 10 years −6% −5% −5% −6% −5% −6% −5% −5% −5%

Surgery and inpatient cost +10% −0.2% −0.2% −0.1% −0.2% −0.3% −0.2% −0.1% −0.2% −0.2%

−10% 0.2% 0.2% 0.1% 0.2% 0.3% 0.2% 0.1% 0.2% 0.2%

Discounting Country specific No discounting −2% −4% −4% −4% −4% −1% −4% −5% −5%

Productivity loss Not calculated Calculated −27% −22% −12% −6% −18% −15% −11% −15% −10%

Utility Lindsay et al., 2008 +10% −9% −9% −9% −9% −9% −9% −9% −9% −9%

−10% 11% 11% 11% 11% 11% 11% 11% 11% 11%

Wasting No wasting Wasting 15% 15% 15% 15% 15% 14% 14% 10% 13%

Age 40 years 35 years 0.1% 0.1% 0.1% 0.3% 0.1% 0.1% 0.1% 0.1% 0.1%

45 years −0.2% −0.2% −0.2% −0.5% −0.1% −0.2% −0.2% −0.1% −0.1%

Regarding parameters relating to the weight dependent dosing of bsIFX and IFX, the ±5 kg change in patients’ weight resulted in a change of ±8% in ICERs. Inclusion of wasting of infliximab vials increased the ICERs by 10–15%.

Probabilistic sensitivity analysis (PSA)

Results were robust for the changed in input data and assumptions. For example in the UK, The 95% confidence intervals of the ICERs calculated by the simulations were €45788–€97677/QALY for bsIFX and €51081–€94182/QALY for IFX, both compared with standard care.

In 69% of the simulations, the ICER of bsIFX remained under a 2 × GDP per capita financial threshold in the UK. This was the case in 56% of the cases for IFX.

Discussion

In this study we assessed the cost-effectiveness of single biologicals and treatment sequences in comparison with non-biological standard care and with each other for adult patients with fistulising active CD in nine European countries. This is the first cost-effectiveness analysis with bsIFX, ADA and VEDO in fistulising CD, and also the first which assessed the cost-effectiveness of biological treatment sequences including two and three biological substances. Nine European countries were involved in the analyses which enables us to make cross-country comparisons. Also, this is the first study to analyse the cost-effectiveness of biologicals in fistulising CD not only from third-party payers but also from the societal perspective.

In scenarios including a single biological drug, bsIFX was the most cost-effective and VEDO was the least cost-effective treatment compared with non-biological standard care. In France, the Netherlands and in Belgium the cost-effectiveness of IFX and bsIFX were identical as the list prices of these two drugs were equal (Table 4). Starting treatment with bsIFX was not only the most cost-effective scenario but also IFX had the highest level of clinical evidence that supports this strategy.

As a second biological treatment following bsIFX, ADA provided better cost-effectiveness results compared with VEDO, except in Germany. Including VEDO as a third agent in the treatment sequence (after bsIFX and ADA) provides high cost-effectiveness ratios.

The use of bsIFX in the treatment sequences instead of IFX, reduces the ICERs to below a threshold of 2 × GDP per capita across all the nine countries. The introduction of bsIFX has made biological treatment more affordable, providing cost-savings, thus it improves access to biological therapy.

The cross-country differences in ICERs can be largely explained by the differences of the list prices of biologicals (i.e. higher biological prices resulting higher ICERs). The highest ICERs were observed in Germany (Table 4) due to the highest list prices (Table 3).

It is important to point out that real purchasing prices are substantially lower than list prices, but are not publicly available, and can vary even within a country due to local tenders. Based on personal communication, the price of bsIFX is about 50% lower than the list price of the originator product. Thus, we performed repeat calculations applying a 30% price decrease for bsIFX and IFX, and a 20% decrease for ADA list prices to get cost-effectiveness ratios which we assume to better reflect real world practice (Table 5). As a result, ICERs decreased by 19–30%, although the optimal treatment strategies remained the same. Using this approach in Germany, ADA became the most cost-effective treatment as a second treatment option after bsIFX.

Comparison with the available three cost-effectiveness studies in fistulising CD is hampered by methodological differences. Arseanau and colleagues (2001) evaluated IFX therapy in comparison with standard care on a one-year time horizon in the USA, and the ICER varied from $355,450 to $377,000/QALY.²³ Clarke and colleagues (2003) analysed IFX against standard care in the UK and the ICERs were between £82,000–£123,000/QALY.²⁴ Lindsay et al. (2008) found a somewhat lower ICER (£29,752 per QALY) with IFX compared with standard care in the UK on a five-year horizon.²⁵

This cost-effectiveness model has several limitations. The model movements represent clinical practice, however we applied some simplifications. We did not calculate with the effects of discontinuation of biological therapy, and assumed that spontaneous healing from the refractory state is only allowed once in the model. In addition, patients could go through surgery a maximum of two times during the full time horizon of the model. Nevertheless, the model results are robust despite these assumptions as they are identical in the active and comparator scenarios. The model focuses on fistulising CD and treatment effects on luminal CD symptoms were not captured. Specifically, we focused on endpoints related to fistula healing in the model and did not take into account the potential improvements in the underlying CD (e.g. improvements in the CDAI score)). Thus, giving conservative estimations, we probably underestimated the efficacy of therapy in case of patients where fistula closure was not achieved but underlying CD activity improved. In these cases larger health gains are achieved on the same costs, resulting better cost-effectiveness ratios.

Due to the lack of data in fistulising CD, we did not calculate with the effects of dose-increases. However, dose increase occurs in everyday clinical practice in fistulising CD.

Transition probabilities between model states are key points in cost-effectiveness modelling. Due to the scarcity of evidence from RCTs we had to apply some estimations. For fistula healing as a primary outcome in RCTs, there is only evidence for IFX. Evidence for ADA and VEDO comes from subgroup analysis of RCTs.

We used country-specific costs in the model. However we could not consider all intercountry variations due to shortage of local data (such as patients’ age, weight and efficacy), thus for some parameters we assumed no significant differences across the countries. Nevertheless, results of our sensitivity analysis suggest that in a country where the average weight of patients is +5 kg, the ICERs increase by about 8%. Results were much less sensitive to changes in the age of patients, ±5 years change results in −0.5% to +0.3% change in the ICERs. Moreover, health status and disease progression of patients initiating biological treatment in the real world might differ between jurisdictions due to variations in health care delivery structures, guidelines, clinical practice (e.g. surgical strategies, the level of multidisciplinary teamwork) and access (availability, affordability and acceptability) to biological treatment.^16,36 These might result in some differences of effectiveness as well, however at a minor level compared with the overall treatment effects. Nevertheless, refinement of our results based on more precise, local evidence is to be encouraged. Our study revealed a remarkable deficiency of data in the literature on fistulising CD patients, a point we suggest should be considered in the development of CD registries and in publication strategies in the future.

In conclusion, as the number of biologicals is growing for fistulising CD the focus of cost-effectiveness analysis is moving to the comparison of treatment sequences. This is the first study which assessed the cost-effectiveness of biological treatment sequences in fistulising CD. We found that bsIFX was the most beneficial first treatment choice in all of the nine countries. Appling a second and third biological provides some additional health gain at a high cost. Significant differences were found in costs but only minor variations in health gains across countries.

Conclusion

In clinical practice, treatment sequences of biologicals are applied for active fistulising CD, however underlying health economic analyses are lacking. The suggested first-choice biological treatment is bsIFX. In case of treatment failure, switching to ADA then to VEDO provides meaningful additional health gains but at increased costs.

Model states	Health state	Therapy	Utility^a
‘A’ Initiation of Biologic Therapy State	H1: Patients with draining fistula(s) with failure to adequate previous conventional treatment or previous biological treatment	T1: induction therapy with biological treatment^b	0.40
‘B’ Complete fistula healing state^c	H2: patients without any fistula	T2: ongoing maintenance biological treatment
		or	0.83
		T3: non-biological standard therapy
‘C’ Incomplete fistula healing state^d	H3: incomplete fistula healing, patients with at least 50% reduction in number of fistulas	T2: ongoing maintenance biological treatment
or	0.68
		T3: non-biological standard therapy
‘D’ Biologic therapy refractory state	H1: Patients with draining fistula(s) with failure to adequate previous treatment	T3: non-biological standard therapy	0.40
‘E’ Surgery state	H1: Patients with draining fistula(s) with failure to adequate previous treatment	T4: major fistula surgery	0.40
‘F’ Post surgery remission state	H2: patients without any fistula	T3: non-biological standard therapy	0.83
‘G’ Death	H4: death	–	–

Item	Substance	Source (references)	Probability projected for model cycles (3 months)	Risk of bias (reason)
Probability of complete healing	Infliximab	Present 1999 5 mg infliximab branch week 18 Projection for week 12⁴	41.1%	Low (primary endpoint)
Adalimumab	Colombel et al., 2009, (Patients with healed fistulas adalimumab every other week (eow) and weekly combined arm 16^th week 36% 20^th week 34% → estimation for 18^th week: 35%) Projection for week 12⁸	25.0%	Medium (subgroup analysis, secondary endpoint)
Vedolizumab	Feagan et al., 2015 Number of patients with fistula closure at 14^th week Table (arm: vedolizumab every 8 weeks): 29,4% Projection for week 12³⁰	25.8%	Medium (subgroup analysis, secondary endpoint)
Placebo	Present et al., 1999 placebo branch⁴	8.8%	Low (primary endpoint)
Probability of incomplete healing	Infliximab	Present et al., 1999 5 mg infliximab branch⁴	8.8%	Low (primary endpoint)
Adalimumab	Estimation based on: Present et al., 1999 and Colombel et al., 2009 (infliximab incomplete healing/complete healing x adalimumab complete healing)^4,8	5.3%	High (estimation, projection from maintenance data, subgroup analysis, secondary endpoint)
Vedolizumab	Estimation based on: Present et al., 1999 and Sandborn et al., 2013 (infliximab incomplete healing/complete healing x vedolizumab complete healing)^4,9	5.5%	High (estimation, projection from maintenance data, subgroup analysis, secondary endpoint)
Placebo	Present 1999 placebo branch⁴	8.8%	Low
Probability of relapse	Infliximab	Sands 2004 infliximab branch (ACCENT II.)⁵	17.6%	Low
	Adalimumab	Estimation: Sands et al., 2004 (efficacy of placebo) and Colombel et al., 2009^5,8 (relative efficacy of adalimumab compared to placebo)	20.1%	Medium (estimation, subgroup analysis, secondary endpoint)
	Vedolizumab	Estimation: Sands et al., 2004 (efficacy of placebo) and Sandborn et al., 2013 (relative efficacy of vedolizumab compared to placebo)^5,9	16.3%	Medium (estimation, subgroup analysis, secondary endpoint)
	Placebo	Sands et al., 2004 placebo branch⁵	30.7%	Low
Probability moving from complete healing to incomplete healing	Infliximab	Calculated based on Sands et al., 2004 (Accent II.)⁵	2.6%	Low
Adalimumab	Estimation based on Sands et al., 2004 and Colombel et al., 2009: infliximab complete healing to incomplete healing/infliximab_relapse x adalimumab_relapse^5,8	2.8%	High (subgroup analysis, secondary endpoint)
Vedolizumab	Estimation based on Sands 2004 and Sandborn 2013: infliximab complete healing to incomplete healing/infliximab_relapse x vedolizumab_relapse^5,9	2.4%	High (subgroup analysis, secondary endpoint)
Placebo	Calculated based on Sands et al., 2004 (Accent II.)⁵	1.0%	Low
Probability of surgery	–	Based on three Cohort studies (Amiot et al., 2014, Molendijk et al., 2014, Pittet et al., 2010)^31–33	15.9%	Low
Probability of surgical remission	–	Based on Yassin et al., 2014 meta-analysis of cohort studies²⁶	10.6%	Low

Item Country	Biosimilar- infliximab 1 × 100 mg	Originator- infliximab 1 × 100 mg	Adalimumab 2 × 40 mg	Vedolizumab 1 × 300 mg
Belgium	€388.87	€388.87	€950.64	€2264.10
France	€434.403	€434.403	€859.38	UK price
Germany	€701.86	€933.67	€1843.77	€2987.97
Hungary	€345.50	€492.14	€881.70	UK Price: €2887.32
Italy	€428.01	€570.68	€1068.56	€2256
Netherlands	€573.99	€573.99	€1144.90	€2235.54
Spain	€510.29	€615.88	€1127.57	€3662.79
Sweden	€450.29	€552.81	€1087.15	€2374.01
UK	€531.92	€591.01	€991.94	€2887.32

	Belgium	France	Germany	Hungary	Italy	Netherlands	Spain	Sweden	UK
St. care
QALY	2.097	2.027	2.031	1.990	2.033	2.100	2.031	2.034	2.007
Cost	12,250	11,786	15,956	3595	15,047	13,717	18,272	33,178	20,273
One biological vs st. care
bsIFX vs st. care
Δ QALY to st. care	0.2524	0.2462	0.2461	0.2436	0.2460	0.2523	0.2461	0.2460	0.2442
Δ cost to st. care	9697	10,764	17,854	8450	10,840	14,910	13,394	17,095	15,603
ICER to st. care	38,420	43,721	72,551	34,684	44,059	59,101	54,427	69,491	63,908
IFX vs st. care
Δ QALY to st. care	0.252	0.246	0.246	0.244	0.246	0.252	0.246	0.246	0.244
Δ cost to st. care	9697	10,764	23,512	12,007	14,322	14,910	15,971	19,597	17,040
ICER to st. care	38,420	43,721	95,540	49,286	58,215	59,101	64,898	79,663	69,793
ADA vs st.care
Δ QALY to st. care	0.136	0.132	0.132	0.131	0.132	0.136	0.132	0.132	0.131
Δ cost to st. care	9091	8151	17,480	7941	10,361	11,411	11,417	14,157	9989
ICER to st. care	66,921	61,562	132,071	60,646	78,296	84,031	86,263	106,990	76,099
VEDO vs st.care
Δ QALY to st. care	0.168	0.164	0.164	0.162	0.164	0.168	0.164	0.164	0.162
Δ cost to st. care	14,117	17,799	18,964	17,504	14,307	14,598	23,295	20,228	20,163
ICER to st. care	83,806	108,561	115,696	108,026	87,299	86,688	142,118	123,437	124,090
Two biologicals vs biosimilar IFX
bsIFX−ADA vs bsIFX
Δ QALY to bsIFX	0.108	0.105	0.105	0.103	0.105	0.108	0.105	0.105	0.104
Δ cost to bsIFX	6963	6129	14,016	6857	7723	8370	8176	8146	6367
ICER to bsIFX	64,223	58,533	133,831	66,589	73,730	77,183	78,068	77,765	61,500
bsIFX−VEDO vs bsIFX
Δ QALY to bsIFX	0.133	0.128	0.128	0.126	0.128	0.133	0.128	0.128	0.127
Δ cost to bsIFX	11,411	14,677	15,285	15,289	11,207	11,157	18,700	13,507	15,374
ICER to bsIFX	85,734	114,294	118,993	121,094	87,231	83,808	145,582	105,126	121,121
Three biologicals vs bsIFX−ADA
bsIFX−ADA−VEDO vs bsIFX−ADA
Δ QALY to bsIFX−ADA	0.120	0.115	0.115	0.113	0.115	0.120	0.115	0.115	0.113
Δ cost to bsIFX−ADA	10,745	13,795	14,361	14,395	10,533	10,444	17,587	12,652	14,434
ICER to bsIFX−ADA	89,775	120,003	124,858	127,732	91,537	87,214	152,901	109,945	127,207

	Belgium	France	Germany	Hungary	Italy	Netherlands	Spain	Sweden	UK
One biological vs st. care
bsIFX vs st. care
Δ cost to st. care	6850	7584	12,716	5936	7705	10,737	9658	13,797	11,724
ICER to st. care	27,141	30,807	51,670	24,364	31,319	42,558	39,245	56,086	48,017
IFX vs st. care
Δ cost to st. care	6850	7584	16,676	8426	10,143	10,737	11,462	15,549	12,729
ICER to st. care	27,141	30,807	67,762	34,585	41,228	42,558	46,575	63,206	52,137
ADA vs st.care
Δ cost to st. care	7398	6621	14,196	6378	8457	9383	9409	12,220	8228
ICER to st. care	54,459	50,005	107,255	48,713	63,912	69,100	71,091	92,354	62,683
Two consecutive biologicals vs bsIFX
bsIFX−ADA vs bsIFX
Δ cost to bsIFX	5455	4765	11,088	5473	6026	6576	6386	6419	4803
ICER to bsIFX	50,309	45,513	105,875	53,151	57,529	60,634	60,977	61,281	46,395

	Base case estimate	Sensitivity estimate	Belgium	France	Germany	Hungary	Italy	Netherlands	Spain	Sweden	UK
Base case			38,420	43,721	72,551	34,684	44,059	59,101	54,427	69,491	63,908
Body weight	65 kg	60 kg	−8%	−8%	−7%	−8%	−7%	−7%	−7%	−5%	−6%
		70 kg	8%	8%	7%	8%	7%	7%	7%	5%	6%
Time horizon	5 years	10 years	−6%	−5%	−5%	−6%	−5%	−6%	−5%	−5%	−5%
Surgery and inpatient cost	+10%	−0.2%	−0.2%	−0.1%	−0.2%	−0.3%	−0.2%	−0.1%	−0.2%	−0.2%
		−10%	0.2%	0.2%	0.1%	0.2%	0.3%	0.2%	0.1%	0.2%	0.2%
Discounting	Country specific	No discounting	−2%	−4%	−4%	−4%	−4%	−1%	−4%	−5%	−5%
Productivity loss	Not calculated	Calculated	−27%	−22%	−12%	−6%	−18%	−15%	−11%	−15%	−10%
Utility	Lindsay et al., 2008	+10%	−9%	−9%	−9%	−9%	−9%	−9%	−9%	−9%	−9%
		−10%	11%	11%	11%	11%	11%	11%	11%	11%	11%
Wasting	No wasting	Wasting	15%	15%	15%	15%	15%	14%	14%	10%	13%
Age	40 years	35 years	0.1%	0.1%	0.1%	0.3%	0.1%	0.1%	0.1%	0.1%	0.1%
		45 years	−0.2%	−0.2%	−0.2%	−0.5%	−0.1%	−0.2%	−0.2%	−0.1%	−0.1%

Footnotes

Conflicts of Interest

PB reports grants from Hospira a Pfizer Company during the conduct of the study; grants from Sager Pharma, grants from Egis Pharma, non-financial support from Astellas, outside the submitted work. LG received consultancy and lecturing fee from Egis Pharmaceutical, Hospira, Pfizer, Celltrion, Sandoz, Astellas. VB reports grants from Hospira a Pfizer Company during the conduct of the study; grants and personal fees from Egis Pharma, personal fees from Sager Pharma, outside the submitted work. ZV reports having received speakers' bureau fees from AbbVie and Takeda. SD has served as a speaker, a consultant and an advisory board member for Schering-Plough, Abbott Laboratories, Merck & Co., UCB Pharma, Ferring, Cellerix, Millenium Takeda, Nycomed, Pharmacosmos, Actelion, Alphawasserman, Genentech, Grunenthal, Pfizer, Astra Zeneca, Hospira, Novo Nordisk, Cosmo Pharmaceuticals, Vifor, and Johnson and Johnson. PMI has received consultancy and lecturing fees from AbbVie, Warner Chilcott, Ferring, Falk Pharma, Takeda, MSD, Janssen, Shire, Vifor, Pharmacosmos, Samsung Bioepis, VH2, Hospira, Genetech. LPB reports personal fees from Abbvie, Janssen, Genentech, Mitsubichi, Ferring, Norgine, Tillots, Vifor, Shire, Pharmacosmos, BMS, UCB-Pharma, Hospira, Takeda, Boerhinger-Ingelheim, Pfizer, Lilly, Celltrion, Merck, Therakos, Pilege, Biogaran, HAC-Pharma, Index-Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, outside the submitted work. SS received consultancy and/or lecturing fees from AbbVie, Biogen, Celltrion, Celgene, Falk, Ferring, Janssen, MSD, Pfizer, Roche, Takeda and UCB. FR reports grants from Astellas, outside the submitted work. PLL reports having received consultancy and lecturing fees from AbbVie, Celltrion, Celgene, Ferring, Hospira, Mitsubichi Tanabe Pharma, MSD, Pfizer, Roche and Takeda. MP reports grants from Hospira a Pfizer Company during the conduct of the study; grants and personal fees from Egis Pharma, Merck, Pfizer, Sager Phama, outside the submitted work.

Funding

This work was supported by an unrestricted grant from Pfizer Hospira UK.

Ethics approval

This is a non-interventional study and ethical approval was not needed. Data were derived from published publicly available articles. No other data sources were used.

Informed consent

Not applicable as patients were not included.

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Cost-effectiveness of biological treatment sequences for fistulising Crohn’s disease across Europe

Abstract

Background

Objective

Methods

Results

Conclusions

Keywords

Key summary

Introduction

Materials and methods

Model overview

Patients

Comparison of treatment sequences

Transition probabilities

Costs and outcomes

Sensitivity analyses

Results

Cost-effectiveness analyses (base case)

Single biologicals compared with standard care – list price

Treatment sequences with two or three biologicals – list prices

Cost-effectiveness with estimated real prices

One-way sensitivity analysis

Probabilistic sensitivity analysis (PSA)

Discussion

Conclusion

Footnotes

Conflicts of Interest

Funding

Ethics approval

Informed consent

References