Therapeutic Drug Monitoring is More Cost-Effective than a Clinically Based Approach in the Management of Loss of Response to Infliximab in Inflammatory Bowel Disease: An Observational Multicentre Study

Therapeutic Drug Monitoring is More Cost-Effective than a Clinically Based Approach in the... Abstract Background and Aims Empirical dose intensification and therapeutic drug monitoring [TDM] of infliximab [IFX] trough levels [ITLs] and antibody to infliximab [ATI] assays are recognized approaches for managing loss of response [LoR] in patients with inflammatory bowel disease [IBD]. The aim of the study was to compare these two interventions in a clinical setting, in terms of effectiveness and cost savings. Methods Consecutive IBD patients experiencing LoR were clinically managed according to a TDM algorithm. A historical group of empirically treated patients, for whom sera for ITLs and ATI assays had been collected, served as the control group. Clinical outcomes 12 weeks after the therapeutic interventions were compared between the two groups. A cost-minimization analysis was performed to compare the economic impact of these two approaches. Results Ninety-six patients were enrolled prospectively and compared with 52 controls. The two cohorts were similar in characteristics and in the distribution of TDM results. In the prospective cohort, however, we observed less IFX dose escalations compared with in the controls [45% versus 71%, p = 0.003]. Also, more patients were switched to a different anti-TNFα in the prospective cohort than in the control cohort [25% versus 4%, p = 0.001]. The percentages of patients achieving a clinical response at 12 weeks were 52% and 54% for the prospective and control groups, respectively. By cost analysis, we estimated a savings of 15% if the TDM algorithm was applied. Conclusions In our population, applying a TDM algorithm for LoR to IFX resulted in less dose escalations, without loss of efficacy, compared with empirical adjustment. In addition, the TDM approach was cost-effective. Biologics, health economics, Crohn’s disease, ulcerative colitis 1. Introduction Anti-TNFα agents are effective drugs for the management of inflammatory bowel disease [IBD]. However, a large percentage of patients develop a loss of response [LoR] that requires physician intervention.1–5 After laboratory, endoscopic, and imaging findings have determined that IBD-related inflammatory mechanisms are the underlying cause of the LoR, two different approaches can be adopted: an empirical clinically driven dose intensification, or individualized management based on a therapeutic drug monitoring [TDM] strategy.6 The latter consists of measuring serum drug trough levels [TLs] and anti-drug antibodies [ADAs]. A clinical decision-making algorithm has been proposed, based on those levels.7–9 The algorithm relies on three key mechanisms for LoR: [1] immunogenicity, related to the development of ADAs neutralizing the drug’s activity and increasing clearance;10–12 [2] variability in pharmacokinetics [influenced by several factors such as disease severity, albumin serum levels, and body mass index, leading to subtherapeutic drug concentrations];12 and [3] variability in pharmacodynamics, probably caused by the activation of alternative [not TNFα-driven] pro-inflammatory pathways.6,13,14 A clinical trial by Steenholdt et al., enrolling 69 infliximab [IFX] secondary failure patients, did not demonstrate that the TDM-approach was superior to an empirical dose intensification [5 mg/kg at 4 weeks] in terms of short-term clinical and biological responses. However, the clinical intervention based on the algorithm avoided inappropriate use of IFX and resulted in a significant cost savings [mean difference per patient of €3141 in the intention-to-treat population].8 However, these results have not been replicated in prospective clinical practice studies. To date, the TDM for LoR is only used routinely in a few IBD referral centres. A widespread empirical IFX dose escalation for all patients who develop a biologic secondary failure could be a huge waste of taxpayers’ money. The aim of our study was to investigate, in a clinical setting, the advantage of a systematic TDM-based approach versus an empirically driven dose escalation, in terms of clinical effectiveness and cost savings in a prospective cohort of patients with LoR to IFX. 2. Methods 2.1. Study design and patient populations A prospective, longitudinal cohort study was conducted, from May 2015 to June 2016, at five Italian tertiary referral IBD centres: four for adult patients [Fondazione Policlinico Universitario A. Gemelli Presidio Columbus; Azienda Ospedaliera San Camillo Forlanini; Campus Bio-medico, Rome; and A.O.U. Pisana, Pisa] and one for paediatric subjects [Pediatria Policlinico Umberto I, Rome]. All patients diagnosed with Crohn’s disease [CD] or ulcerative colitis [UC],15 who were on maintenance therapy with IFX for at least 4 months and experienced LoR, were considered for inclusion in the study. For this study, LoR was defined as worsening or relapsing of symptoms and at least one of the following: a C-reactive protein [CRP] level >5 mg/L; faecal calprotectin >150 µg/g; or endoscopic, ultrasound, or radiological findings of active disease. The following baseline variables were collected: age, gender, type of disease, extent of disease, concomitant use of immunomodulators [i.e. thiopurines or methotrexate], duration of IFX maintenance therapy, use of biosimilar drugs [CT-P13], and CRP serum levels. Disease extent was defined according to the Montreal classification.16 The serum of eligible patients was used to determine IFX trough levels [ITLs] and antibodies to infliximab [ATIs]. All serum samples were assayed by ELISA [Lisa Tracker-Duo® Infliximab, Theradiag, Marne-la-Vallée, France]. The cut-off for therapeutic ITLs and detectable ATIs were established at 3 μg/mL and 10 ng/mL, respectively, according to literature data17–22 and the manufacturer’s instructions. Therapeutic interventions were established according to an algorithm adapted from Steenholdt et al.8 defining four potential scenarios [Table 1]. The IFX dose escalation group [Group 1] included either an increase in the IFX dosage to 10 mg/kg or the reduction of the interval between infusions to 4 weeks. Group 2 included any potential treatment change [steroids, immunosuppressive therapies, surgery, enrolment in clinical trials, withdrawal of anti-TNFα and even no treatment change except for IFX dose escalation and the switch to a second anti-TNFα]. Patients in Group 3 were switched to a different anti-TNFα. In case of therapeutic ITLs and detectable ATIs [Group 4], patients had to be retested and reclassified accordingly. Table 1. Modified therapeutic algorithm for IBD patients with LoR to IFX. Group 1 Group 2 ITL <3 μg/mL >3 μg/mL ATI <10 ng/mL <10 ng/mL Therapeutic intervention Increase IFX dose and/or reduce interval between infusions Change treatment [another class of biologic, immunosuppressant, steroid, surgery] Group 3 Group 4 ITL <3 μg/mL >3 μg/mL ATI >10 ng/mL >10 ng/mL Therapeutic intervention Switch to a different anti-TNFα Repeat measurement of ITL and ATI and reclassify Group 1 Group 2 ITL <3 μg/mL >3 μg/mL ATI <10 ng/mL <10 ng/mL Therapeutic intervention Increase IFX dose and/or reduce interval between infusions Change treatment [another class of biologic, immunosuppressant, steroid, surgery] Group 3 Group 4 ITL <3 μg/mL >3 μg/mL ATI >10 ng/mL >10 ng/mL Therapeutic intervention Switch to a different anti-TNFα Repeat measurement of ITL and ATI and reclassify View Large Table 1. Modified therapeutic algorithm for IBD patients with LoR to IFX. Group 1 Group 2 ITL <3 μg/mL >3 μg/mL ATI <10 ng/mL <10 ng/mL Therapeutic intervention Increase IFX dose and/or reduce interval between infusions Change treatment [another class of biologic, immunosuppressant, steroid, surgery] Group 3 Group 4 ITL <3 μg/mL >3 μg/mL ATI >10 ng/mL >10 ng/mL Therapeutic intervention Switch to a different anti-TNFα Repeat measurement of ITL and ATI and reclassify Group 1 Group 2 ITL <3 μg/mL >3 μg/mL ATI <10 ng/mL <10 ng/mL Therapeutic intervention Increase IFX dose and/or reduce interval between infusions Change treatment [another class of biologic, immunosuppressant, steroid, surgery] Group 3 Group 4 ITL <3 μg/mL >3 μg/mL ATI >10 ng/mL >10 ng/mL Therapeutic intervention Switch to a different anti-TNFα Repeat measurement of ITL and ATI and reclassify View Large After clinical interventions, patients were prospectively followed for up to 12 weeks and then were clinically re-evaluated to establish the clinical effectiveness of each therapeutic intervention. Clinical response was defined as a decrease from baseline as follows: [1] a decrease in the Partial Mayo Score [PMS]23 ≥ 2 points and ≥ 30% plus a decrease in the rectal bleeding subscore [RBS] ≥ 1 or an absolute RBS ≤ 1, for UC patients; and [2] a decrease in the Harvey–Bradshaw Index [HBI]24 ≥ 3 points, for CD patients, plus a drop in CRP serum levels or faecal calprotectin. To compare the two management approaches [TDM-based versus clinically based dose escalation], we identified a historical group of adult patients, who experienced LoR to IFX between June 2012 and February 2015, from the IBD Centre of Presidio Columbus. This group was used as the controls. For these patients, serum samples for ITLs and ATIs were collected at the diagnosis of LoR, then stored and analysed at least 3 months later. Therefore, the clinical interventions were decided without knowing those results. The protocol was approved by the local Ethics Committee, and all enrolled patients gave written informed consent. 2.2. Cost analysis We performed a cost-minimization analysis, using the activity-based costing [ABC] method to compare the two management approaches for the 12-week study interval.25 The time-driven ABC approach valorizes human resources according to the time spent by the health professionals at each stage of the drug delivery process under analysis. We pre-defined the following time-points: T–1 visit: diagnosis of LoR and TL/ITL assay; T0 visit: therapeutic intervention according to the algorithm or clinical decision, depending on the group; T1 visit: clinical assessment 8 weeks later; T2 visit: clinical assessment 12 weeks from T0. Based on the perspective of the Italian National Health Service [NHS], only direct health-care costs were included in the analysis. To identify the possible savings from the implementation of the therapeutic alternatives based on the algorithm, only differential costs determined by the comparison of the two therapeutic pathways were investigated, ignoring the common costs of both approaches. Costs were calculated in euros [€] and standardized across both recruitment periods. The cost drivers of the therapy administration were computed according to the results emerging from the mapped administration process [T1 to T2]; in particular, each phase was valorized by the consumption value of therapy cost, of human resources, and of materials used for the therapy delivery process [Tables 2 and 3]. Four main drivers of differential costs were identified: [1] cost of specialist medical visit, estimated according to the Italian NHS tariff; [2] cost of TL and ITL assays, amounting to €80; [3] cost of each therapy; and [4] cost of the materials and resources [including human ones] for the administration of therapies and patient follow-up, according to the actual use. To calculate the expenditure for drugs, we considered the ex-factory prices, assuming a median body weight for an adult patient of 70 kilograms [kg] and the dosages reported in each data sheet. The cost of the originator [Remicade] was considered in the principal analysis. In order to provide a more complete evaluation, we also calculated the saving obtainable in two other scenarios: Scenario 1: 100% of the patients receive biosimilar drugs; Scenario 2: 50% of the patients receive biosimilar drugs, 50% receive IFX originator [Table 2]. We estimated, for each intravenous infusion, that the materials cost was €14.94 for materials [physiological solution, hydrophilic cotton, alcohol, sodium chloride solution, infusion bag, infusion sets, lifecycle pump, sterile plastic gloves, syringe and butterfly needle], and the hospital waste management cost was 0.96 €/kg, according to the regional standard rate.26,27 For human resources, the cost was calculated using estimates through direct monitoring of the percentage of time spent on each of the activities by hospital personnel [including gastroenterologist, nurse, and pharmacist] through a time-driven ABC approach.28 The valorization of such time consumption was made on the basis of the cost/minute of each health professional considering the local NHS labour contracts. Finally, a common cost [overhead] equal to 20% of the total consumption of resources, based on a sampling survey carried out in another Italian Region, was added to the aforementioned costs.29 A weighted-average cost was calculated by multiplying the direct cost of each patient plus the cost of each therapeutic intervention by their proportional weight for both two groups. Conventional therapies [e.g. steroids and immunomodulators] included in the ‘Other’ sample group, may not generate direct health-care costs, depending on their administration. Consequently, with regard to conventional treatments, only costs incurred by the hospital due to follow-up visits over the 12 weeks were accounted for. In the ‘Other’ group, there were also cases of therapeutic withdrawal not associated with a consumption of resources, as well as inclusion in clinical trials. Once the direct health costs for each patient were defined for the therapeutic regimen followed over the 12 weeks, we calculated the cost-weighted average of the two different treatment scenarios. Table 2. Therapy cost of the active principles under analysis. Therapy Package Therapy Cost/unit Remicade [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg/kg i.v. every 8 weeks €2 060.16 10 mg/kg i.v. every 8 weeks €3 605.28 Biosimilar CT-P13 [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 545.12 10 mg / kg i.v. every 8 weeks €3 090.23 50% Remicade 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 818.09 50% Biosimilar 10 mg / kg i.v. every 8 weeks €3 154.62 Humira [adalimumab] 2 syringes 40 mg + 2 pads 160 mg €1 825.00 80 mg €912.50 40 mg €456.25 First two doses: 160 mg and 80 mg, followed by a 40 mg dose every 2 weeks Other Steroids Daily cost based on the dosage indicated by Key Opinion Leader €3.81 Immunomodulators €2.34 Therapy suspension €– Therapy Package Therapy Cost/unit Remicade [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg/kg i.v. every 8 weeks €2 060.16 10 mg/kg i.v. every 8 weeks €3 605.28 Biosimilar CT-P13 [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 545.12 10 mg / kg i.v. every 8 weeks €3 090.23 50% Remicade 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 818.09 50% Biosimilar 10 mg / kg i.v. every 8 weeks €3 154.62 Humira [adalimumab] 2 syringes 40 mg + 2 pads 160 mg €1 825.00 80 mg €912.50 40 mg €456.25 First two doses: 160 mg and 80 mg, followed by a 40 mg dose every 2 weeks Other Steroids Daily cost based on the dosage indicated by Key Opinion Leader €3.81 Immunomodulators €2.34 Therapy suspension €– View Large Table 2. Therapy cost of the active principles under analysis. Therapy Package Therapy Cost/unit Remicade [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg/kg i.v. every 8 weeks €2 060.16 10 mg/kg i.v. every 8 weeks €3 605.28 Biosimilar CT-P13 [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 545.12 10 mg / kg i.v. every 8 weeks €3 090.23 50% Remicade 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 818.09 50% Biosimilar 10 mg / kg i.v. every 8 weeks €3 154.62 Humira [adalimumab] 2 syringes 40 mg + 2 pads 160 mg €1 825.00 80 mg €912.50 40 mg €456.25 First two doses: 160 mg and 80 mg, followed by a 40 mg dose every 2 weeks Other Steroids Daily cost based on the dosage indicated by Key Opinion Leader €3.81 Immunomodulators €2.34 Therapy suspension €– Therapy Package Therapy Cost/unit Remicade [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg/kg i.v. every 8 weeks €2 060.16 10 mg/kg i.v. every 8 weeks €3 605.28 Biosimilar CT-P13 [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 545.12 10 mg / kg i.v. every 8 weeks €3 090.23 50% Remicade 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 818.09 50% Biosimilar 10 mg / kg i.v. every 8 weeks €3 154.62 Humira [adalimumab] 2 syringes 40 mg + 2 pads 160 mg €1 825.00 80 mg €912.50 40 mg €456.25 First two doses: 160 mg and 80 mg, followed by a 40 mg dose every 2 weeks Other Steroids Daily cost based on the dosage indicated by Key Opinion Leader €3.81 Immunomodulators €2.34 Therapy suspension €– View Large Table 3. Time and costs activity matrix for Infliximab and Adalimumab [one administration]*. Human resources [HR] Infliximab Adalimumab HR cost /min Time of administration process†[min] Total time [min] Total cost/ HR HR cost [min] Time of administration process†[min] Total time [min] Total cost/ HR Admission Supplying Patient preparation Medical examination Drug preparation Infusion Discharge Admission Supplying Patient preparation Medical examination Drug preparation Gastroenterologist 1.38 30 10 2 42 57.94 1.38 10 10 13.79 Nurse 0.44 1 10 10 120 141 62.04 0.44 2.27 10 12.27 5.40 Pharmacist 0.92 2 2 1.84 0.92 15 2.27 17.27 15.86 Administrative support 0.33 2 2 0.65 0.33 2.27 2.27 0.74 Total cost/phase 0.66 2.28 45.80 13.80 4.40 52.80 2.76 121.00 0.75 14.80 4.40 13.80 2.09 35.79 Materials consumed Unit cost Consumption Total consumption Total cost Unit cost Consumption Total consumption Total cost Infusion-chair 3.00 1 1 3.00 3.00 0 0 Infusion material cost‡ 16.44 1 1 16.44 14.94 0 Waste disposal hospital treated [ROT] [kg] 0.96 0.1 0.1 0.10 Overhead [20% of total amount] 37.23 45.98 0.96 0 Administration cost/ patient 186.15 37.23 35.79 Human resources [HR] Infliximab Adalimumab HR cost /min Time of administration process†[min] Total time [min] Total cost/ HR HR cost [min] Time of administration process†[min] Total time [min] Total cost/ HR Admission Supplying Patient preparation Medical examination Drug preparation Infusion Discharge Admission Supplying Patient preparation Medical examination Drug preparation Gastroenterologist 1.38 30 10 2 42 57.94 1.38 10 10 13.79 Nurse 0.44 1 10 10 120 141 62.04 0.44 2.27 10 12.27 5.40 Pharmacist 0.92 2 2 1.84 0.92 15 2.27 17.27 15.86 Administrative support 0.33 2 2 0.65 0.33 2.27 2.27 0.74 Total cost/phase 0.66 2.28 45.80 13.80 4.40 52.80 2.76 121.00 0.75 14.80 4.40 13.80 2.09 35.79 Materials consumed Unit cost Consumption Total consumption Total cost Unit cost Consumption Total consumption Total cost Infusion-chair 3.00 1 1 3.00 3.00 0 0 Infusion material cost‡ 16.44 1 1 16.44 14.94 0 Waste disposal hospital treated [ROT] [kg] 0.96 0.1 0.1 0.10 Overhead [20% of total amount] 37.23 45.98 0.96 0 Administration cost/ patient 186.15 37.23 35.79 *All costs are expressed in € [VAT included]; †per patient. ‡Saline, hydrophilic cotton, disinfectant solution, infusion bag, infusion set, lifecare pump, sterile plastic gloves, syringe and butterfly needle View Large Table 3. Time and costs activity matrix for Infliximab and Adalimumab [one administration]*. Human resources [HR] Infliximab Adalimumab HR cost /min Time of administration process†[min] Total time [min] Total cost/ HR HR cost [min] Time of administration process†[min] Total time [min] Total cost/ HR Admission Supplying Patient preparation Medical examination Drug preparation Infusion Discharge Admission Supplying Patient preparation Medical examination Drug preparation Gastroenterologist 1.38 30 10 2 42 57.94 1.38 10 10 13.79 Nurse 0.44 1 10 10 120 141 62.04 0.44 2.27 10 12.27 5.40 Pharmacist 0.92 2 2 1.84 0.92 15 2.27 17.27 15.86 Administrative support 0.33 2 2 0.65 0.33 2.27 2.27 0.74 Total cost/phase 0.66 2.28 45.80 13.80 4.40 52.80 2.76 121.00 0.75 14.80 4.40 13.80 2.09 35.79 Materials consumed Unit cost Consumption Total consumption Total cost Unit cost Consumption Total consumption Total cost Infusion-chair 3.00 1 1 3.00 3.00 0 0 Infusion material cost‡ 16.44 1 1 16.44 14.94 0 Waste disposal hospital treated [ROT] [kg] 0.96 0.1 0.1 0.10 Overhead [20% of total amount] 37.23 45.98 0.96 0 Administration cost/ patient 186.15 37.23 35.79 Human resources [HR] Infliximab Adalimumab HR cost /min Time of administration process†[min] Total time [min] Total cost/ HR HR cost [min] Time of administration process†[min] Total time [min] Total cost/ HR Admission Supplying Patient preparation Medical examination Drug preparation Infusion Discharge Admission Supplying Patient preparation Medical examination Drug preparation Gastroenterologist 1.38 30 10 2 42 57.94 1.38 10 10 13.79 Nurse 0.44 1 10 10 120 141 62.04 0.44 2.27 10 12.27 5.40 Pharmacist 0.92 2 2 1.84 0.92 15 2.27 17.27 15.86 Administrative support 0.33 2 2 0.65 0.33 2.27 2.27 0.74 Total cost/phase 0.66 2.28 45.80 13.80 4.40 52.80 2.76 121.00 0.75 14.80 4.40 13.80 2.09 35.79 Materials consumed Unit cost Consumption Total consumption Total cost Unit cost Consumption Total consumption Total cost Infusion-chair 3.00 1 1 3.00 3.00 0 0 Infusion material cost‡ 16.44 1 1 16.44 14.94 0 Waste disposal hospital treated [ROT] [kg] 0.96 0.1 0.1 0.10 Overhead [20% of total amount] 37.23 45.98 0.96 0 Administration cost/ patient 186.15 37.23 35.79 *All costs are expressed in € [VAT included]; †per patient. ‡Saline, hydrophilic cotton, disinfectant solution, infusion bag, infusion set, lifecare pump, sterile plastic gloves, syringe and butterfly needle View Large 2.3. Statistical analysis Data were described using medians with interquartile ranges [IQRs] for continuous data, and percentages for discrete data. Baseline characteristics and TLs plus ITL assessments of patients from prospective and control groups were compared using t-tests, Mann–Whitney tests, χ2, and Fisher exact tests as appropriate. Correlations were explored using Spearman’s rank test. The proportion of patients with a clinical response 12 weeks after the therapeutic interventions in the TDM-based group was compared with that in the control group using the χ2 test and expressed as the absolute difference with 95% confidence intervals [CIs]. A p value of less than 0.05 was considered statistically significant. A one-way deterministic sensitivity analysis [OWSA] was conducted that considered the intrinsic variability of the data employed in the model.30 Such analysis involves a deterministic approach in which the model results fluctuate based on the variation of a given parameter at one time, according to changes reported in the literature or assumed by the authors. In this case, we excluded all cost drivers derived by the time-based ABC, such as the time spent by the professionals involved in the administration process, with variations that did not significantly impact the end results. We also performed a probabilistic sensitivity analysis [PSA], with 10 000 Monte-Carlo simulations, associating each category of variables considered in the economic model with their range of variability extrapolated from the literature or assumed by the clinicians. A cost-acceptance curve was developed to represent the results achieved in the PSA.31 In order to account for the uncertainty surrounding the value of the parameters included in both the one-way and the multiway sensitivity analyses, a standard deviation equal to 20% of the variable’s values was associated with each item. Furthermore, a normal distribution was associated with all the cost drivers monitored in the model, while clinical drivers were associated with a beta distribution [Table 4]. Analyses were performed with MedCalc Statistical Software, 9.2.1.0 [MedCalc software bvba, Ostende, Belgium] and Microsoft Excel with Visual Basic for Applications. Table 4. Parameters and distributions considered in the probabilistic sensitivity analysis [PSA]. Clinical drivers Base-case a b Min Max Distr. Treatment Prospective % Beta  Dose escalation IFX [%] 45% 0.79 0.97 18% 71%  Switch to other anti-TNFα [Adalimumab] [%] 25% 0.69 2.06 6% 39%  Other [%] 30% 0.75 1.74 9% 47%  Total 100% – – – – Other  Steroids 8% 0.28 3.34 0% 10%  Immunomodulators 42% 0.80 1.09 16% 66%  IFX withdrawal 15% 0.50 2.73 2% 23%  No treatment change [IFX 5MG] 8% 0.28 3.34 0% 10%  Surgery 12% 0.39 3.03 1% 17%  Other biologic drug 15% 0.50 2.73 2% 23% Cost drivers [IFX] Gastroenterologist Minutes  Patient preparation 30 – – 25.95 34.05 Normal  Medical examination 10 – – 8.65 11.35  Discharge 2 – – 1.73 2.27 Nurse  Drug provision 1 – – 0.87 1.13  Patient preparation 10 – – 8.65 11.35  Drug preparation 10 – – 8.65 11.35  Infusion 120 – – 103.81 136.19 Pharmacist  Drug provision 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 Cost drivers [ADA] Gastroenterologist  Medical examination 10 – – 8.65 11.35 Nurse  Drug provision 2 – – 1.73 2.27  Patient preparation 10 – – 8.65 11.35  Dispensation 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 Clinical drivers Base-case a b Min Max Distr. Treatment Prospective % Beta  Dose escalation IFX [%] 45% 0.79 0.97 18% 71%  Switch to other anti-TNFα [Adalimumab] [%] 25% 0.69 2.06 6% 39%  Other [%] 30% 0.75 1.74 9% 47%  Total 100% – – – – Other  Steroids 8% 0.28 3.34 0% 10%  Immunomodulators 42% 0.80 1.09 16% 66%  IFX withdrawal 15% 0.50 2.73 2% 23%  No treatment change [IFX 5MG] 8% 0.28 3.34 0% 10%  Surgery 12% 0.39 3.03 1% 17%  Other biologic drug 15% 0.50 2.73 2% 23% Cost drivers [IFX] Gastroenterologist Minutes  Patient preparation 30 – – 25.95 34.05 Normal  Medical examination 10 – – 8.65 11.35  Discharge 2 – – 1.73 2.27 Nurse  Drug provision 1 – – 0.87 1.13  Patient preparation 10 – – 8.65 11.35  Drug preparation 10 – – 8.65 11.35  Infusion 120 – – 103.81 136.19 Pharmacist  Drug provision 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 Cost drivers [ADA] Gastroenterologist  Medical examination 10 – – 8.65 11.35 Nurse  Drug provision 2 – – 1.73 2.27  Patient preparation 10 – – 8.65 11.35  Dispensation 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 View Large Table 4. Parameters and distributions considered in the probabilistic sensitivity analysis [PSA]. Clinical drivers Base-case a b Min Max Distr. Treatment Prospective % Beta  Dose escalation IFX [%] 45% 0.79 0.97 18% 71%  Switch to other anti-TNFα [Adalimumab] [%] 25% 0.69 2.06 6% 39%  Other [%] 30% 0.75 1.74 9% 47%  Total 100% – – – – Other  Steroids 8% 0.28 3.34 0% 10%  Immunomodulators 42% 0.80 1.09 16% 66%  IFX withdrawal 15% 0.50 2.73 2% 23%  No treatment change [IFX 5MG] 8% 0.28 3.34 0% 10%  Surgery 12% 0.39 3.03 1% 17%  Other biologic drug 15% 0.50 2.73 2% 23% Cost drivers [IFX] Gastroenterologist Minutes  Patient preparation 30 – – 25.95 34.05 Normal  Medical examination 10 – – 8.65 11.35  Discharge 2 – – 1.73 2.27 Nurse  Drug provision 1 – – 0.87 1.13  Patient preparation 10 – – 8.65 11.35  Drug preparation 10 – – 8.65 11.35  Infusion 120 – – 103.81 136.19 Pharmacist  Drug provision 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 Cost drivers [ADA] Gastroenterologist  Medical examination 10 – – 8.65 11.35 Nurse  Drug provision 2 – – 1.73 2.27  Patient preparation 10 – – 8.65 11.35  Dispensation 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 Clinical drivers Base-case a b Min Max Distr. Treatment Prospective % Beta  Dose escalation IFX [%] 45% 0.79 0.97 18% 71%  Switch to other anti-TNFα [Adalimumab] [%] 25% 0.69 2.06 6% 39%  Other [%] 30% 0.75 1.74 9% 47%  Total 100% – – – – Other  Steroids 8% 0.28 3.34 0% 10%  Immunomodulators 42% 0.80 1.09 16% 66%  IFX withdrawal 15% 0.50 2.73 2% 23%  No treatment change [IFX 5MG] 8% 0.28 3.34 0% 10%  Surgery 12% 0.39 3.03 1% 17%  Other biologic drug 15% 0.50 2.73 2% 23% Cost drivers [IFX] Gastroenterologist Minutes  Patient preparation 30 – – 25.95 34.05 Normal  Medical examination 10 – – 8.65 11.35  Discharge 2 – – 1.73 2.27 Nurse  Drug provision 1 – – 0.87 1.13  Patient preparation 10 – – 8.65 11.35  Drug preparation 10 – – 8.65 11.35  Infusion 120 – – 103.81 136.19 Pharmacist  Drug provision 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 Cost drivers [ADA] Gastroenterologist  Medical examination 10 – – 8.65 11.35 Nurse  Drug provision 2 – – 1.73 2.27  Patient preparation 10 – – 8.65 11.35  Dispensation 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 View Large 3. Results 3.1. Patients’ characteristics Ninety-six consecutive IBD [56 CD, 40 UC] patients who developed LoR to IFX were prospectively enrolled. Twelve patients were included from the paediatric centre [median age 15 years, range 6–17]. Fifty-two patients [28 CD, 24 UC] were included in the control group. The demographic and clinical characteristics of patients from both groups are shown in Table 5. No significant differences were found in terms of gender, age, type or extent of disease, dose or duration of IFX therapy, concomitant use of immunomodulators, or in the baseline CRP value between the two groups. However, a minority of patients [12%] were treated with IFX biosimilars in the prospective cohort. Table 5. Patients’ characteristics. Prospective cohort [n = 96] Control group [n = 52] p Crohn’s disease n [%] 56 [58] 28 [54] 0.60 Male n [%] 51 [53] 24 [46] 0.49 Age [years, mean, 95% CI] 38.9 [35.3–42.4] 42.7 [38.8–42.6] 0.18 Montreal classification A1; A2; A3 12; 35; 9 6; 18; 4 L1; L2; L3; p 12; 18; 26; 17 7; 11; 10; 10 B1; B2; B3 22; 25; 9 11; 14; 3 E1; E2; E3 5; 12; 23 0; 8; 16 Duration of IFX therapy [months, median, IQR] 17 [6.5–28.5] 17 [7–40] 0.63 Biosimilars n [%] 12 [12] 0 [0] 0.004 Immunomodulators n [%] 19 [20] 12 [23] 0.67 CRP mg/dL [median, IQR] 5 [2.9–7] 6.7 [3.3–9.5] 0.52 IFX trough levels [μg/mL] median [IQR] 1.7 [0.6–9.6] 3.4 [0.6–9.4] 0.08 Antibodies to IFX [ng/mL] median [IQR] 6.3 [2.7–13.9] 7 [4.3–25] 0.08 Prospective cohort [n = 96] Control group [n = 52] p Crohn’s disease n [%] 56 [58] 28 [54] 0.60 Male n [%] 51 [53] 24 [46] 0.49 Age [years, mean, 95% CI] 38.9 [35.3–42.4] 42.7 [38.8–42.6] 0.18 Montreal classification A1; A2; A3 12; 35; 9 6; 18; 4 L1; L2; L3; p 12; 18; 26; 17 7; 11; 10; 10 B1; B2; B3 22; 25; 9 11; 14; 3 E1; E2; E3 5; 12; 23 0; 8; 16 Duration of IFX therapy [months, median, IQR] 17 [6.5–28.5] 17 [7–40] 0.63 Biosimilars n [%] 12 [12] 0 [0] 0.004 Immunomodulators n [%] 19 [20] 12 [23] 0.67 CRP mg/dL [median, IQR] 5 [2.9–7] 6.7 [3.3–9.5] 0.52 IFX trough levels [μg/mL] median [IQR] 1.7 [0.6–9.6] 3.4 [0.6–9.4] 0.08 Antibodies to IFX [ng/mL] median [IQR] 6.3 [2.7–13.9] 7 [4.3–25] 0.08 View Large Table 5. Patients’ characteristics. Prospective cohort [n = 96] Control group [n = 52] p Crohn’s disease n [%] 56 [58] 28 [54] 0.60 Male n [%] 51 [53] 24 [46] 0.49 Age [years, mean, 95% CI] 38.9 [35.3–42.4] 42.7 [38.8–42.6] 0.18 Montreal classification A1; A2; A3 12; 35; 9 6; 18; 4 L1; L2; L3; p 12; 18; 26; 17 7; 11; 10; 10 B1; B2; B3 22; 25; 9 11; 14; 3 E1; E2; E3 5; 12; 23 0; 8; 16 Duration of IFX therapy [months, median, IQR] 17 [6.5–28.5] 17 [7–40] 0.63 Biosimilars n [%] 12 [12] 0 [0] 0.004 Immunomodulators n [%] 19 [20] 12 [23] 0.67 CRP mg/dL [median, IQR] 5 [2.9–7] 6.7 [3.3–9.5] 0.52 IFX trough levels [μg/mL] median [IQR] 1.7 [0.6–9.6] 3.4 [0.6–9.4] 0.08 Antibodies to IFX [ng/mL] median [IQR] 6.3 [2.7–13.9] 7 [4.3–25] 0.08 Prospective cohort [n = 96] Control group [n = 52] p Crohn’s disease n [%] 56 [58] 28 [54] 0.60 Male n [%] 51 [53] 24 [46] 0.49 Age [years, mean, 95% CI] 38.9 [35.3–42.4] 42.7 [38.8–42.6] 0.18 Montreal classification A1; A2; A3 12; 35; 9 6; 18; 4 L1; L2; L3; p 12; 18; 26; 17 7; 11; 10; 10 B1; B2; B3 22; 25; 9 11; 14; 3 E1; E2; E3 5; 12; 23 0; 8; 16 Duration of IFX therapy [months, median, IQR] 17 [6.5–28.5] 17 [7–40] 0.63 Biosimilars n [%] 12 [12] 0 [0] 0.004 Immunomodulators n [%] 19 [20] 12 [23] 0.67 CRP mg/dL [median, IQR] 5 [2.9–7] 6.7 [3.3–9.5] 0.52 IFX trough levels [μg/mL] median [IQR] 1.7 [0.6–9.6] 3.4 [0.6–9.4] 0.08 Antibodies to IFX [ng/mL] median [IQR] 6.3 [2.7–13.9] 7 [4.3–25] 0.08 View Large 3.2. ITL and ATI assessment and therapeutic interventions The median ITLs and ATI levels were comparable for the two groups [Table 5]. However, the baseline ITLs were numerically lower in the prospective cohort compared with in the control group [p = 0.08]. No relevant correlations were found between the ITLs or the ATIs with IBD type, sex, age, duration of therapy with IFX, concomitant use of immunomodulators, or CRP values at inclusion. There were no differences with respect to the distributions into the four groups of the algorithm [Table 6]. With regard to therapeutic interventions, the management of LoR significantly differed between the two groups. The rate of IFX dose escalation was significantly lower in the TDM-based group compared with in the control group [43/96, 45% vs 37/52, 71%, respectively; p = 0.003]. Conversely, a significantly greater percentage of patients switched to a second anti-TNFα in the TDM group [24/96, 25% in the TDM-based group vs 2/52, 4% in the control group; p = 0.001]. The two cohorts did not differ according to the use of other therapeutic interventions [p = 0.56] [Supplementary Materials Table 1]. There was a correspondence between the theoretical algorithm–based intervention and the performed therapeutic interventions in 63% of cases in the prospective cohort compared with 39% in the retrospective cohort [p = 0.00053]. Fifty-three percent of the escalations [23/43] were performed in concordance with the theoretical algorithm in the prospective cohort, compared with 24% [9/37] in the control group [p = 0.011] [Table 7]. Table 6. Distribution of patients into the groups of the therapeutic algorithm. Group Prospective cohort n [%] Control group n [%] p 1 28 [29] 14 [27] 0.84 2 36 [38] 19 [36.5] 1 3 28 [29] 13 [25] 0.70 4 4 [4] 6 [11.5] 0.17 Group Prospective cohort n [%] Control group n [%] p 1 28 [29] 14 [27] 0.84 2 36 [38] 19 [36.5] 1 3 28 [29] 13 [25] 0.70 4 4 [4] 6 [11.5] 0.17 View Large Table 6. Distribution of patients into the groups of the therapeutic algorithm. Group Prospective cohort n [%] Control group n [%] p 1 28 [29] 14 [27] 0.84 2 36 [38] 19 [36.5] 1 3 28 [29] 13 [25] 0.70 4 4 [4] 6 [11.5] 0.17 Group Prospective cohort n [%] Control group n [%] p 1 28 [29] 14 [27] 0.84 2 36 [38] 19 [36.5] 1 3 28 [29] 13 [25] 0.70 4 4 [4] 6 [11.5] 0.17 View Large Table 7. Therapeutic interventions and correspondence with the algorithm. Therapeutic interventions Prospective cohort n [%] Control group n [%] p Dose escalation 43 [45] 37 [71] 0.003 Switch to a 2nd anti-TNFα 24 [25] 2 [4] 0.001 Other 29 [30] 13 [25] 0.56 Total correspondence to algorithm 60 [63] 17 [39] 0.00053 Dose escalation in accordance with algorithm 23 [53] 9 [24] 0.011 Therapeutic interventions Prospective cohort n [%] Control group n [%] p Dose escalation 43 [45] 37 [71] 0.003 Switch to a 2nd anti-TNFα 24 [25] 2 [4] 0.001 Other 29 [30] 13 [25] 0.56 Total correspondence to algorithm 60 [63] 17 [39] 0.00053 Dose escalation in accordance with algorithm 23 [53] 9 [24] 0.011 View Large Table 7. Therapeutic interventions and correspondence with the algorithm. Therapeutic interventions Prospective cohort n [%] Control group n [%] p Dose escalation 43 [45] 37 [71] 0.003 Switch to a 2nd anti-TNFα 24 [25] 2 [4] 0.001 Other 29 [30] 13 [25] 0.56 Total correspondence to algorithm 60 [63] 17 [39] 0.00053 Dose escalation in accordance with algorithm 23 [53] 9 [24] 0.011 Therapeutic interventions Prospective cohort n [%] Control group n [%] p Dose escalation 43 [45] 37 [71] 0.003 Switch to a 2nd anti-TNFα 24 [25] 2 [4] 0.001 Other 29 [30] 13 [25] 0.56 Total correspondence to algorithm 60 [63] 17 [39] 0.00053 Dose escalation in accordance with algorithm 23 [53] 9 [24] 0.011 View Large 3.3. Clinical outcome Three patients in the prospective group did not complete the 12-week assessment because surgery was needed during the study interval. There was a clinical response 12 weeks from the therapeutic intervention in 52% [48/93, 95% CI 42–61%] of patients in the prospective group compared with 54% [28/52, 95% CI 40–67%] in the control group [p = 1]. No significant differences in terms of clinical response were found between the two groups, when patients were subdivided according to the clinical interventions adopted [Supplementary Materials Table 2]. 3.4. Cost analysis The analysis of the unit costs, calculated as the sum of the activity-based monitoring costs, administration costs, and drug costs over the 12-week investigation for each therapeutic intervention, showed that the IFX dose escalation was associated with greater resource costs. As far as the cost of treatments is concerned, the aforementioned results imply that at least 25% of the dose escalation in the retrospective cohort could have been avoided without any clinical repercussions. Thus, if the therapeutic interventions had been based on the theoretical algorithm for all 145 patients from both cohorts [excluding the three who did not complete the study], it would have allowed a saving of €128 648.13 [–15%, Table 8], namely, ~€887/patient over the 12 weeks of treatment. Furthermore, the savings determined in the analysis were higher than the costs for the administration of the TDM test. In fact, for the control group, the cost of IFX dose escalation, equal to €282 669.04, could have been reduced by 15% [€42 400.36], as the total cost for the TDM assay was €4160. When biosimilars of IFX were included in the analysis, in Scenario 1 [100% biosimilar] the percentage of the saving generated was reduced by 10% compared with the base case [15%] and equal to 5%; in Scenario 2 [50% originator, 50% biosimilar], the saving was reduced by 3% compared with the base case, lowering it to 12%. Table 8. Total cost/patient for each therapeutic intervention and the cost savings calculated as the difference between the total costs of the empirical and TDM approaches for a sample of 145 patients. Total cost/patient for each strategy Dose escalation 2nd anti-TNFα [adalimumab] Other Total cost [145 patients] Control group [%] 71% 4% 25% Cost empirical approach €7 639.70 €5 095.41 €1 588.73 €874 219.77 Prospective cohort [%] 45% 25% 30% Cost TDM approach €7 719.70 €5 175.41 €889.14 €745 571.64 Differential €128 648.13 Saving TDM 15% Total cost/patient for each strategy Dose escalation 2nd anti-TNFα [adalimumab] Other Total cost [145 patients] Control group [%] 71% 4% 25% Cost empirical approach €7 639.70 €5 095.41 €1 588.73 €874 219.77 Prospective cohort [%] 45% 25% 30% Cost TDM approach €7 719.70 €5 175.41 €889.14 €745 571.64 Differential €128 648.13 Saving TDM 15% View Large Table 8. Total cost/patient for each therapeutic intervention and the cost savings calculated as the difference between the total costs of the empirical and TDM approaches for a sample of 145 patients. Total cost/patient for each strategy Dose escalation 2nd anti-TNFα [adalimumab] Other Total cost [145 patients] Control group [%] 71% 4% 25% Cost empirical approach €7 639.70 €5 095.41 €1 588.73 €874 219.77 Prospective cohort [%] 45% 25% 30% Cost TDM approach €7 719.70 €5 175.41 €889.14 €745 571.64 Differential €128 648.13 Saving TDM 15% Total cost/patient for each strategy Dose escalation 2nd anti-TNFα [adalimumab] Other Total cost [145 patients] Control group [%] 71% 4% 25% Cost empirical approach €7 639.70 €5 095.41 €1 588.73 €874 219.77 Prospective cohort [%] 45% 25% 30% Cost TDM approach €7 719.70 €5 175.41 €889.14 €745 571.64 Differential €128 648.13 Saving TDM 15% View Large According to the deterministic sensitivity analysis, the main cost driver that affected the difference between the two approaches was the percentage of patients undergoing IFX dose escalation, since its increase resulted in an important decline in terms of savings. The same trend, with a less significant magnitude, was observed for an increase in the percentage of patients who switched to another anti-TNFα [adalimumab] [Figure 1]. The results of the PSA are shown in Figure 2. The curve has a steep slope and demonstrates that the introduction of the proposed algorithm in clinical practice generates savings and is likely to generate higher savings than those achieved in the base case [–15%]. In particular, the analysis shows a probability of >80% associated with the employment of the algorithm [compared with the standard care] of generating a >10% decrease in expenditure. Figure 1. View largeDownload slide One-way sensitivity analysis: IFX dose escalation vs TDM approach. Figure 1. View largeDownload slide One-way sensitivity analysis: IFX dose escalation vs TDM approach. Figure 2. View largeDownload slide Probabilistic savings curve: IFX dose escalation vs TDM approach. Figure 2. View largeDownload slide Probabilistic savings curve: IFX dose escalation vs TDM approach. In order to facilitate the comparability of the economic results achieved in the present analysis with those of other studies already realized in different settings, a threshold analysis was carried out in order to determine the price of IFX, concerning which the policy-maker is indifferent between the two therapeutic paths. In particular, the analysis showed that the price of IFX originator, which is 25% higher than the biosimilar version, would need to be reduced by >40% in order to make null the savings the TDM approach would guarantee. 4. Discussion The present study demonstrated that, for patients with LoR to IFX, an individualized management based on TDM was more cost-effective than an empirical IFX dose escalation in clinical practice. The TDM approach was based on a previously described algorithm,8 guiding physicians’ therapeutic interventions based on the ITL and ATI results. However, we adopted a higher threshold for detecting ITLs than the Danish trial [3 μg/mL vs 0.5 μg/mL, respectively], to limit the mislabelling of patients. Accordingly, patients with ITLs of ≥0.5 and ≤3 μg/mL, without ATIs, were suitable for an IFX dose escalation, rather than a change in the anti-TNFα class, which may lead to mechanistic failure [up to 70%].8,32 The percentage of patients who received therapeutic interventions according to the theoretical algorithm was similar in our study and in the Danish trial [63% versus 59%]. To our knowledge, our study is the first conducted in a clinical practice setting, with a prospective design and an a priori establishment of cut-offs for the ITLs and ATIs, that uses a therapeutic intervention algorithm and includes a control group. Three previous observational studies explored the role of TDM for managing anti-TNFα [both IFX and adalimumab] in secondary-failure patients.9,33,34 However, in these studies, patients were empirically managed, and the outcome of the clinical interventions was related a posteriori to the TLs of drugs and ADAs during LoR. Our study confirmed that the two strategies were equivalent in terms of the short-term clinical and biological responses. Recently, Kelly et al. retrospectively compared data from two cohorts of IFX-treated patients undergoing dose escalations at their centre: one group was TDM-guided and one was based on clinical data without TDM. After a median follow-up of 6 months, the authors observed a higher rate of endoscopic remission [63% vs 48%, p < 0.005] and clinical response [69% vs 57%, p < 0.001] and lower rate of hospitalization [22% vs 35%, p = 0.025] in the TDM group compared with in the empirical one.35 By our cost analysis, the TDM approach resulted in a significant cost savings, estimated at €128 648.13 [15%, Table 7, Supplementary Materials Figure 1] or ~€887/patient over the 12 weeks of treatment. The main cost driver was the percentage of patients undergoing IFX dose escalation, which was significantly higher in the empirical group [71% vs 45%, respectively, p = 0.003] and only partially necessary according to the algorithm [53% vs 24%, p = 0.011] [Table 7]. Interestingly, the baseline ITLs were numerically lower in the prospective cohort compared with in the empirical group, and this gap, although not significant, might have impacted on the difference in the proportions of patients having dose escalation. Recently Martelli et al.36 performed a systematic review comparing the cost-effectiveness of TDM vs the empirical approach for the management of IBD and rheumatoid arthritis [RA] patients treated with anti-TNFα. Seven studies were included: two randomized controlled trials on IBD8,37 and five studies using a modelling approach [Roblin et al. pers. comm., and four cited references].38–41 All the studies showed that the TDM strategy is more cost-effective than an empirical one in IBD and RA patients, with no negative impact on efficacy. The main limitation of our study was its non-randomized nature and the use of an historical population as a control group. Moreover, the major use of an IFX biosimilar [used by only 12% of patients from the prospective cohort] could significantly reduce the costs related to therapy. In relation to this, we simulated in two additional scenarios the use of an IFX biosimilar by 50% and 100% patients, and we still obtained significant savings by the use of TDM approach [–12% and –5%, respectively]. The cut-off values adopted in the present study were chosen according to the data available at the time of study design. However, a higher threshold for ITLs has recently been suggested.32 We then performed a subgroup analysis of Group 2 [patients with adequate ITLs and negative ADAs]. The median ITL of Group 2 patients was 7.4 μg/mL [IQR 5.6–10.9]: this value is higher than the recently defined cut-off of 5 μg/mL.32 Moreover, vedolizumab [VDZ] has only been commercially available in Italy for treating IBD patients since the second half of 2016. To date, VDZ is the first biologic, non-targeting TNF-α available and represents the best choice for patients who develop a mechanistic LoR [Group 2 in our cohort]. The inclusion of VDZ in our analysis could have significantly influenced the costs. Nevertheless, because the percentage of patients in Group 2 in both cohorts eligible for a switch to VDZ was similar [38% and 36%, Table 2], the impact on cost would have been comparable; thus, the optimization of IFX would remain the primary driver of the budget impact. Furthermore, in the empirical setting, the switch would probably be done after failing a period of IFX optimization, with increased costs. Our cost analysis included drug-related costs as well as the costs of specialist medical visits and of each material and resource [including human resources] for therapy administration and patient follow-up, according to current consumption. Our cost analysis, furthermore, was limited to medical treatments, as the three patients who underwent surgery were excluded from the evaluation. The two studied groups were recruited in different locations and over different time periods: this could have affected the results, although we recorded a good adherence to the study protocol in the prospectively recruited cohort. Finally, our study did not take into account the addition of an immunomodulator to the infliximab therapy. Some recent reports have suggested the utility of this strategy, in order to reduce ATIs and increase ITLs.42 A recently published consensus statement depicts a more complex scenario, in which ATI titres [low versus high] are considered and combination therapy with immunomodulators is advised in case of subtherapeutic ITLs and low ATIs.43 The cost-effectiveness of this approach should be addressed with an adequately powered study. With regard to ATI assay, we employed a drug-sensitive ELISA. By this method we found, in our populations, 86 patients [57 in the prospective group and 29 in the control group] with circulating IFX and ATI levels under the limit of detection or inconclusive. The usefulness of a drug-tolerant assay, as compared with a drug-sensitive one, has been extensively debated in recent years. However, the most recently published guidelines corroborate our approach, stating that there is insufficient evidence to recommend a drug-tolerant assay for anti-drug antibody detection.43 In conclusion, in a clinical practice setting, the TDM strategy for IFX secondary-failure patients was more cost-effective than an empirical approach, with similar clinical effectiveness. Therefore, physicians and health-care authorities should promote TDM in clinical practice, to best allocate the economic resources in the face of growing use of biologic therapies. The possibility of extending these conclusions to adalimumab or to other biologics cannot, however, be confirmed by extrapolating our data, and it should be addressed by appropriate research. Finally, given the observational nature of our study and the use of historical controls, these results should be replicated in a randomized prospective study that, at variance with the Danish trial,8 should include the recently defined ‘therapeutic’ cut-off values for ITLs. Supplementary Data Supplementary data are available at ECCO-JCC online. Funding The study was financed with grants from Catholic University of Sacred Heart, line D1, years 2013 and 2016. Conflict of Interest LG: Consultant for AbbVie, MSD, Mundipharma, Takeda; lecture fees from AbbVie, Janssen, MSD, Mundipharma, Takeda, Vifor Pharma, Zambon. DP: Lecture fees from AbbVie, MSD, Takeda. LC: Consultant for MSD. AA: Consultant for AbbVie, Allergan, Biogen, Celgene, Celltrion, Ferring, Hospira, Janssen, Lilly, MSD, Mundipharma, Pfizer, Samsung, Sofar, Takeda; Lecture fees from AbbVie, AstraZeneca, Chiesi, Ferring, Hospira, Janssen, MSD, Mitsubishi Tanabe, Mundipharma, Nikkiso, Pfizer, Otsuka, Takeda, Tigenix, Zambon; Research grants from MSD. The remaining authors have no conflict of interest to disclose. Author Contributions LG, DP, AA: Study concept, design and supervision, and guarantor of the article; LG, DP,TPT, BT, LC, PB, FC, LB, MM, CF, FC, FV, MC, AK: acquisition of data; LG, DP, TPT, AB, MB, MR: analysis and interpretation of data; LG, DP: drafting of the manuscript; AA, AG, GLR, EG: revision of the manuscript for important intellectual content. All authors approved the final version of the manuscript. References 1. Allez M , Karmiris K , Louis E , et al. 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Regione Lazio - Direzione Regionale Centrale Acquisti . Determinazione Gara Farmaci 2013 fornitura triennale – n. G05177 del 17/12/2013 . http://www.regione.lazio.it/binary/rl_main/tbl_contenuti/bandi_x_legislatura/Atti_amministrativi/Medicinali_2013/determinazione_approvazione_graduatoria.pdf. Accessed September 15, 2017. 27. Regione Piemonte . Settore Programmazione e gestione rifiuti. Indagine sui rifiuti sanitari prodotti in Piemonte ; 2011 . http://www.regione.piemonte.it/ambiente/rifiuti/dwd/RifiutiSanitari/relazione_sanitari_2008_MUD2009_11aprile2011.pdf. Accessed September 15, 2017. 28. Kaplan RS , Anderson SR . Time-driven activity-based costing . Harv Bus Rev 2004 ; 82 : 131 – 8 . Google Scholar PubMed 29. Colombo GL , Muzio A , Longhi A . Valutazione economica di Infliximab [Remicade®] vs Etanercept [Enbrel®] nel trattamento dell’artrite reumatoide . Farmeconomia e percorsi terapeutici 2003 ; 4 : 189 – 98 . 30. Limwattananon S . Handling uncertainty of the economic evaluation result: sensitivity analysis . J Med Assoc Thai 2008 ; 91 : S59 – 65 . Google Scholar PubMed 31. Doubilet P , Begg CB , Weinstein MC , et al. Probabilistic sensitivity analysis using Monte Carlo simulation: a practical approach . Med Decis Making 1985 ; 5 : 157 – 77 . Google Scholar CrossRef Search ADS PubMed 32. Vande Casteele N , Herfarth H , et al. American Gastroenterological Association Institute technical review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases . Gastroenterology 2017 ; 153 : 835 – 57 . Google Scholar CrossRef Search ADS PubMed 33. Paul S , Del Tedesco E , Marotte H , et al. Therapeutic drug monitoring of infliximab and mucosal healing in inflammatory bowel disease: a prospective study . Inflamm Bowel Dis 2013 ; 19 : 2568 – 76 . Google Scholar CrossRef Search ADS PubMed 34. Roblin X , Rinaudo M , Del Tedesco E , et al. Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases . Am J Gastroenterol 2014 ; 109 : 1250 – 6 . Google Scholar CrossRef Search ADS PubMed 35. Kelly OB , Donnell SO , Stempak JM , et al. Therapeutic drug monitoring to guide infliximab dose adjustment is associated with better endoscopic outcomes than clinical decision making alone in active inflammatory bowel disease . Inflamm Bowel Dis 2017 ; 23 : 1202 – 9 . Google Scholar CrossRef Search ADS PubMed 36. Martelli L , Olivera P , Roblin X , et al. Cost-effectiveness of drug monitoring of anti-TNF therapy in inflammatory bowel disease and rheumatoid arthritis: a systematic review . J Gastroenterol 2017 ; 52 : 19 – 25 . Google Scholar CrossRef Search ADS PubMed 37. Vande Casteele N , Ferrante M , Van Assche G , et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease . Gastroenterology 2015 ; 148 : 1320 – 9 . Google Scholar CrossRef Search ADS PubMed 38. Velayos FS , Kahn JG , Sandborn WJ , et al. A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn’s disease who lose responsiveness to infliximab . Clin Gastroenterol Hepatol 2013 ; 11 : 654 – 66 . Google Scholar CrossRef Search ADS PubMed 39. Roblin X , Attar A , Lamure M , et al. Cost savings of anti-TNF therapy using a test-based strategy versus an empirical dose escalation in Crohn’s disease patients who lose response to infliximab . J Mark Access Health Policy 2015 ; 3 : 10.3402/jmahp.v3.29229 . https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802699/pdf/JMAHP-3-29229.pdf. Accessed September 1, 2017. 40. Krieckaert CL , Nair SC , Nurmohamed MT , et al. Personalised treatment using serum drug levels of adalimumab in patients with rheumatoid arthritis: an evaluation of costs and effects . Ann Rheum Dis 2015 ; 74 : 361 – 8 . Google Scholar CrossRef Search ADS PubMed 41. Laine J , Jokiranta TS , Eklund KK , et al. Cost-effectiveness of routine measuring of serum drug concentrations and anti-drug antibodies in treatment of rheumatoid arthritis patients with TNFa blockers . Biol Targets Ther 2016 ; 10 : 67 – 73 . Google Scholar CrossRef Search ADS 42. Ben-Horin S , Waterman M , Kopylov U , et al. Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease . Clin Gastroenterol Hepatol 2013 ; 11 : 444 – 7 . Google Scholar CrossRef Search ADS PubMed 43. Mitrev N , Vande Casteele N , Seow CH , et al. Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases . Aliment Pharmacol Ther 2017 : 1037 – 53 . Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

Therapeutic Drug Monitoring is More Cost-Effective than a Clinically Based Approach in the Management of Loss of Response to Infliximab in Inflammatory Bowel Disease: An Observational Multicentre Study

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Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1873-9946
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10.1093/ecco-jcc/jjy076
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Abstract

Abstract Background and Aims Empirical dose intensification and therapeutic drug monitoring [TDM] of infliximab [IFX] trough levels [ITLs] and antibody to infliximab [ATI] assays are recognized approaches for managing loss of response [LoR] in patients with inflammatory bowel disease [IBD]. The aim of the study was to compare these two interventions in a clinical setting, in terms of effectiveness and cost savings. Methods Consecutive IBD patients experiencing LoR were clinically managed according to a TDM algorithm. A historical group of empirically treated patients, for whom sera for ITLs and ATI assays had been collected, served as the control group. Clinical outcomes 12 weeks after the therapeutic interventions were compared between the two groups. A cost-minimization analysis was performed to compare the economic impact of these two approaches. Results Ninety-six patients were enrolled prospectively and compared with 52 controls. The two cohorts were similar in characteristics and in the distribution of TDM results. In the prospective cohort, however, we observed less IFX dose escalations compared with in the controls [45% versus 71%, p = 0.003]. Also, more patients were switched to a different anti-TNFα in the prospective cohort than in the control cohort [25% versus 4%, p = 0.001]. The percentages of patients achieving a clinical response at 12 weeks were 52% and 54% for the prospective and control groups, respectively. By cost analysis, we estimated a savings of 15% if the TDM algorithm was applied. Conclusions In our population, applying a TDM algorithm for LoR to IFX resulted in less dose escalations, without loss of efficacy, compared with empirical adjustment. In addition, the TDM approach was cost-effective. Biologics, health economics, Crohn’s disease, ulcerative colitis 1. Introduction Anti-TNFα agents are effective drugs for the management of inflammatory bowel disease [IBD]. However, a large percentage of patients develop a loss of response [LoR] that requires physician intervention.1–5 After laboratory, endoscopic, and imaging findings have determined that IBD-related inflammatory mechanisms are the underlying cause of the LoR, two different approaches can be adopted: an empirical clinically driven dose intensification, or individualized management based on a therapeutic drug monitoring [TDM] strategy.6 The latter consists of measuring serum drug trough levels [TLs] and anti-drug antibodies [ADAs]. A clinical decision-making algorithm has been proposed, based on those levels.7–9 The algorithm relies on three key mechanisms for LoR: [1] immunogenicity, related to the development of ADAs neutralizing the drug’s activity and increasing clearance;10–12 [2] variability in pharmacokinetics [influenced by several factors such as disease severity, albumin serum levels, and body mass index, leading to subtherapeutic drug concentrations];12 and [3] variability in pharmacodynamics, probably caused by the activation of alternative [not TNFα-driven] pro-inflammatory pathways.6,13,14 A clinical trial by Steenholdt et al., enrolling 69 infliximab [IFX] secondary failure patients, did not demonstrate that the TDM-approach was superior to an empirical dose intensification [5 mg/kg at 4 weeks] in terms of short-term clinical and biological responses. However, the clinical intervention based on the algorithm avoided inappropriate use of IFX and resulted in a significant cost savings [mean difference per patient of €3141 in the intention-to-treat population].8 However, these results have not been replicated in prospective clinical practice studies. To date, the TDM for LoR is only used routinely in a few IBD referral centres. A widespread empirical IFX dose escalation for all patients who develop a biologic secondary failure could be a huge waste of taxpayers’ money. The aim of our study was to investigate, in a clinical setting, the advantage of a systematic TDM-based approach versus an empirically driven dose escalation, in terms of clinical effectiveness and cost savings in a prospective cohort of patients with LoR to IFX. 2. Methods 2.1. Study design and patient populations A prospective, longitudinal cohort study was conducted, from May 2015 to June 2016, at five Italian tertiary referral IBD centres: four for adult patients [Fondazione Policlinico Universitario A. Gemelli Presidio Columbus; Azienda Ospedaliera San Camillo Forlanini; Campus Bio-medico, Rome; and A.O.U. Pisana, Pisa] and one for paediatric subjects [Pediatria Policlinico Umberto I, Rome]. All patients diagnosed with Crohn’s disease [CD] or ulcerative colitis [UC],15 who were on maintenance therapy with IFX for at least 4 months and experienced LoR, were considered for inclusion in the study. For this study, LoR was defined as worsening or relapsing of symptoms and at least one of the following: a C-reactive protein [CRP] level >5 mg/L; faecal calprotectin >150 µg/g; or endoscopic, ultrasound, or radiological findings of active disease. The following baseline variables were collected: age, gender, type of disease, extent of disease, concomitant use of immunomodulators [i.e. thiopurines or methotrexate], duration of IFX maintenance therapy, use of biosimilar drugs [CT-P13], and CRP serum levels. Disease extent was defined according to the Montreal classification.16 The serum of eligible patients was used to determine IFX trough levels [ITLs] and antibodies to infliximab [ATIs]. All serum samples were assayed by ELISA [Lisa Tracker-Duo® Infliximab, Theradiag, Marne-la-Vallée, France]. The cut-off for therapeutic ITLs and detectable ATIs were established at 3 μg/mL and 10 ng/mL, respectively, according to literature data17–22 and the manufacturer’s instructions. Therapeutic interventions were established according to an algorithm adapted from Steenholdt et al.8 defining four potential scenarios [Table 1]. The IFX dose escalation group [Group 1] included either an increase in the IFX dosage to 10 mg/kg or the reduction of the interval between infusions to 4 weeks. Group 2 included any potential treatment change [steroids, immunosuppressive therapies, surgery, enrolment in clinical trials, withdrawal of anti-TNFα and even no treatment change except for IFX dose escalation and the switch to a second anti-TNFα]. Patients in Group 3 were switched to a different anti-TNFα. In case of therapeutic ITLs and detectable ATIs [Group 4], patients had to be retested and reclassified accordingly. Table 1. Modified therapeutic algorithm for IBD patients with LoR to IFX. Group 1 Group 2 ITL <3 μg/mL >3 μg/mL ATI <10 ng/mL <10 ng/mL Therapeutic intervention Increase IFX dose and/or reduce interval between infusions Change treatment [another class of biologic, immunosuppressant, steroid, surgery] Group 3 Group 4 ITL <3 μg/mL >3 μg/mL ATI >10 ng/mL >10 ng/mL Therapeutic intervention Switch to a different anti-TNFα Repeat measurement of ITL and ATI and reclassify Group 1 Group 2 ITL <3 μg/mL >3 μg/mL ATI <10 ng/mL <10 ng/mL Therapeutic intervention Increase IFX dose and/or reduce interval between infusions Change treatment [another class of biologic, immunosuppressant, steroid, surgery] Group 3 Group 4 ITL <3 μg/mL >3 μg/mL ATI >10 ng/mL >10 ng/mL Therapeutic intervention Switch to a different anti-TNFα Repeat measurement of ITL and ATI and reclassify View Large Table 1. Modified therapeutic algorithm for IBD patients with LoR to IFX. Group 1 Group 2 ITL <3 μg/mL >3 μg/mL ATI <10 ng/mL <10 ng/mL Therapeutic intervention Increase IFX dose and/or reduce interval between infusions Change treatment [another class of biologic, immunosuppressant, steroid, surgery] Group 3 Group 4 ITL <3 μg/mL >3 μg/mL ATI >10 ng/mL >10 ng/mL Therapeutic intervention Switch to a different anti-TNFα Repeat measurement of ITL and ATI and reclassify Group 1 Group 2 ITL <3 μg/mL >3 μg/mL ATI <10 ng/mL <10 ng/mL Therapeutic intervention Increase IFX dose and/or reduce interval between infusions Change treatment [another class of biologic, immunosuppressant, steroid, surgery] Group 3 Group 4 ITL <3 μg/mL >3 μg/mL ATI >10 ng/mL >10 ng/mL Therapeutic intervention Switch to a different anti-TNFα Repeat measurement of ITL and ATI and reclassify View Large After clinical interventions, patients were prospectively followed for up to 12 weeks and then were clinically re-evaluated to establish the clinical effectiveness of each therapeutic intervention. Clinical response was defined as a decrease from baseline as follows: [1] a decrease in the Partial Mayo Score [PMS]23 ≥ 2 points and ≥ 30% plus a decrease in the rectal bleeding subscore [RBS] ≥ 1 or an absolute RBS ≤ 1, for UC patients; and [2] a decrease in the Harvey–Bradshaw Index [HBI]24 ≥ 3 points, for CD patients, plus a drop in CRP serum levels or faecal calprotectin. To compare the two management approaches [TDM-based versus clinically based dose escalation], we identified a historical group of adult patients, who experienced LoR to IFX between June 2012 and February 2015, from the IBD Centre of Presidio Columbus. This group was used as the controls. For these patients, serum samples for ITLs and ATIs were collected at the diagnosis of LoR, then stored and analysed at least 3 months later. Therefore, the clinical interventions were decided without knowing those results. The protocol was approved by the local Ethics Committee, and all enrolled patients gave written informed consent. 2.2. Cost analysis We performed a cost-minimization analysis, using the activity-based costing [ABC] method to compare the two management approaches for the 12-week study interval.25 The time-driven ABC approach valorizes human resources according to the time spent by the health professionals at each stage of the drug delivery process under analysis. We pre-defined the following time-points: T–1 visit: diagnosis of LoR and TL/ITL assay; T0 visit: therapeutic intervention according to the algorithm or clinical decision, depending on the group; T1 visit: clinical assessment 8 weeks later; T2 visit: clinical assessment 12 weeks from T0. Based on the perspective of the Italian National Health Service [NHS], only direct health-care costs were included in the analysis. To identify the possible savings from the implementation of the therapeutic alternatives based on the algorithm, only differential costs determined by the comparison of the two therapeutic pathways were investigated, ignoring the common costs of both approaches. Costs were calculated in euros [€] and standardized across both recruitment periods. The cost drivers of the therapy administration were computed according to the results emerging from the mapped administration process [T1 to T2]; in particular, each phase was valorized by the consumption value of therapy cost, of human resources, and of materials used for the therapy delivery process [Tables 2 and 3]. Four main drivers of differential costs were identified: [1] cost of specialist medical visit, estimated according to the Italian NHS tariff; [2] cost of TL and ITL assays, amounting to €80; [3] cost of each therapy; and [4] cost of the materials and resources [including human ones] for the administration of therapies and patient follow-up, according to the actual use. To calculate the expenditure for drugs, we considered the ex-factory prices, assuming a median body weight for an adult patient of 70 kilograms [kg] and the dosages reported in each data sheet. The cost of the originator [Remicade] was considered in the principal analysis. In order to provide a more complete evaluation, we also calculated the saving obtainable in two other scenarios: Scenario 1: 100% of the patients receive biosimilar drugs; Scenario 2: 50% of the patients receive biosimilar drugs, 50% receive IFX originator [Table 2]. We estimated, for each intravenous infusion, that the materials cost was €14.94 for materials [physiological solution, hydrophilic cotton, alcohol, sodium chloride solution, infusion bag, infusion sets, lifecycle pump, sterile plastic gloves, syringe and butterfly needle], and the hospital waste management cost was 0.96 €/kg, according to the regional standard rate.26,27 For human resources, the cost was calculated using estimates through direct monitoring of the percentage of time spent on each of the activities by hospital personnel [including gastroenterologist, nurse, and pharmacist] through a time-driven ABC approach.28 The valorization of such time consumption was made on the basis of the cost/minute of each health professional considering the local NHS labour contracts. Finally, a common cost [overhead] equal to 20% of the total consumption of resources, based on a sampling survey carried out in another Italian Region, was added to the aforementioned costs.29 A weighted-average cost was calculated by multiplying the direct cost of each patient plus the cost of each therapeutic intervention by their proportional weight for both two groups. Conventional therapies [e.g. steroids and immunomodulators] included in the ‘Other’ sample group, may not generate direct health-care costs, depending on their administration. Consequently, with regard to conventional treatments, only costs incurred by the hospital due to follow-up visits over the 12 weeks were accounted for. In the ‘Other’ group, there were also cases of therapeutic withdrawal not associated with a consumption of resources, as well as inclusion in clinical trials. Once the direct health costs for each patient were defined for the therapeutic regimen followed over the 12 weeks, we calculated the cost-weighted average of the two different treatment scenarios. Table 2. Therapy cost of the active principles under analysis. Therapy Package Therapy Cost/unit Remicade [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg/kg i.v. every 8 weeks €2 060.16 10 mg/kg i.v. every 8 weeks €3 605.28 Biosimilar CT-P13 [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 545.12 10 mg / kg i.v. every 8 weeks €3 090.23 50% Remicade 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 818.09 50% Biosimilar 10 mg / kg i.v. every 8 weeks €3 154.62 Humira [adalimumab] 2 syringes 40 mg + 2 pads 160 mg €1 825.00 80 mg €912.50 40 mg €456.25 First two doses: 160 mg and 80 mg, followed by a 40 mg dose every 2 weeks Other Steroids Daily cost based on the dosage indicated by Key Opinion Leader €3.81 Immunomodulators €2.34 Therapy suspension €– Therapy Package Therapy Cost/unit Remicade [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg/kg i.v. every 8 weeks €2 060.16 10 mg/kg i.v. every 8 weeks €3 605.28 Biosimilar CT-P13 [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 545.12 10 mg / kg i.v. every 8 weeks €3 090.23 50% Remicade 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 818.09 50% Biosimilar 10 mg / kg i.v. every 8 weeks €3 154.62 Humira [adalimumab] 2 syringes 40 mg + 2 pads 160 mg €1 825.00 80 mg €912.50 40 mg €456.25 First two doses: 160 mg and 80 mg, followed by a 40 mg dose every 2 weeks Other Steroids Daily cost based on the dosage indicated by Key Opinion Leader €3.81 Immunomodulators €2.34 Therapy suspension €– View Large Table 2. Therapy cost of the active principles under analysis. Therapy Package Therapy Cost/unit Remicade [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg/kg i.v. every 8 weeks €2 060.16 10 mg/kg i.v. every 8 weeks €3 605.28 Biosimilar CT-P13 [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 545.12 10 mg / kg i.v. every 8 weeks €3 090.23 50% Remicade 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 818.09 50% Biosimilar 10 mg / kg i.v. every 8 weeks €3 154.62 Humira [adalimumab] 2 syringes 40 mg + 2 pads 160 mg €1 825.00 80 mg €912.50 40 mg €456.25 First two doses: 160 mg and 80 mg, followed by a 40 mg dose every 2 weeks Other Steroids Daily cost based on the dosage indicated by Key Opinion Leader €3.81 Immunomodulators €2.34 Therapy suspension €– Therapy Package Therapy Cost/unit Remicade [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg/kg i.v. every 8 weeks €2 060.16 10 mg/kg i.v. every 8 weeks €3 605.28 Biosimilar CT-P13 [infliximab] 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 545.12 10 mg / kg i.v. every 8 weeks €3 090.23 50% Remicade 1 vial powder 100 mg + 1 vial 2 mL 5 mg / kg i.v. every 8 weeks €1 818.09 50% Biosimilar 10 mg / kg i.v. every 8 weeks €3 154.62 Humira [adalimumab] 2 syringes 40 mg + 2 pads 160 mg €1 825.00 80 mg €912.50 40 mg €456.25 First two doses: 160 mg and 80 mg, followed by a 40 mg dose every 2 weeks Other Steroids Daily cost based on the dosage indicated by Key Opinion Leader €3.81 Immunomodulators €2.34 Therapy suspension €– View Large Table 3. Time and costs activity matrix for Infliximab and Adalimumab [one administration]*. Human resources [HR] Infliximab Adalimumab HR cost /min Time of administration process†[min] Total time [min] Total cost/ HR HR cost [min] Time of administration process†[min] Total time [min] Total cost/ HR Admission Supplying Patient preparation Medical examination Drug preparation Infusion Discharge Admission Supplying Patient preparation Medical examination Drug preparation Gastroenterologist 1.38 30 10 2 42 57.94 1.38 10 10 13.79 Nurse 0.44 1 10 10 120 141 62.04 0.44 2.27 10 12.27 5.40 Pharmacist 0.92 2 2 1.84 0.92 15 2.27 17.27 15.86 Administrative support 0.33 2 2 0.65 0.33 2.27 2.27 0.74 Total cost/phase 0.66 2.28 45.80 13.80 4.40 52.80 2.76 121.00 0.75 14.80 4.40 13.80 2.09 35.79 Materials consumed Unit cost Consumption Total consumption Total cost Unit cost Consumption Total consumption Total cost Infusion-chair 3.00 1 1 3.00 3.00 0 0 Infusion material cost‡ 16.44 1 1 16.44 14.94 0 Waste disposal hospital treated [ROT] [kg] 0.96 0.1 0.1 0.10 Overhead [20% of total amount] 37.23 45.98 0.96 0 Administration cost/ patient 186.15 37.23 35.79 Human resources [HR] Infliximab Adalimumab HR cost /min Time of administration process†[min] Total time [min] Total cost/ HR HR cost [min] Time of administration process†[min] Total time [min] Total cost/ HR Admission Supplying Patient preparation Medical examination Drug preparation Infusion Discharge Admission Supplying Patient preparation Medical examination Drug preparation Gastroenterologist 1.38 30 10 2 42 57.94 1.38 10 10 13.79 Nurse 0.44 1 10 10 120 141 62.04 0.44 2.27 10 12.27 5.40 Pharmacist 0.92 2 2 1.84 0.92 15 2.27 17.27 15.86 Administrative support 0.33 2 2 0.65 0.33 2.27 2.27 0.74 Total cost/phase 0.66 2.28 45.80 13.80 4.40 52.80 2.76 121.00 0.75 14.80 4.40 13.80 2.09 35.79 Materials consumed Unit cost Consumption Total consumption Total cost Unit cost Consumption Total consumption Total cost Infusion-chair 3.00 1 1 3.00 3.00 0 0 Infusion material cost‡ 16.44 1 1 16.44 14.94 0 Waste disposal hospital treated [ROT] [kg] 0.96 0.1 0.1 0.10 Overhead [20% of total amount] 37.23 45.98 0.96 0 Administration cost/ patient 186.15 37.23 35.79 *All costs are expressed in € [VAT included]; †per patient. ‡Saline, hydrophilic cotton, disinfectant solution, infusion bag, infusion set, lifecare pump, sterile plastic gloves, syringe and butterfly needle View Large Table 3. Time and costs activity matrix for Infliximab and Adalimumab [one administration]*. Human resources [HR] Infliximab Adalimumab HR cost /min Time of administration process†[min] Total time [min] Total cost/ HR HR cost [min] Time of administration process†[min] Total time [min] Total cost/ HR Admission Supplying Patient preparation Medical examination Drug preparation Infusion Discharge Admission Supplying Patient preparation Medical examination Drug preparation Gastroenterologist 1.38 30 10 2 42 57.94 1.38 10 10 13.79 Nurse 0.44 1 10 10 120 141 62.04 0.44 2.27 10 12.27 5.40 Pharmacist 0.92 2 2 1.84 0.92 15 2.27 17.27 15.86 Administrative support 0.33 2 2 0.65 0.33 2.27 2.27 0.74 Total cost/phase 0.66 2.28 45.80 13.80 4.40 52.80 2.76 121.00 0.75 14.80 4.40 13.80 2.09 35.79 Materials consumed Unit cost Consumption Total consumption Total cost Unit cost Consumption Total consumption Total cost Infusion-chair 3.00 1 1 3.00 3.00 0 0 Infusion material cost‡ 16.44 1 1 16.44 14.94 0 Waste disposal hospital treated [ROT] [kg] 0.96 0.1 0.1 0.10 Overhead [20% of total amount] 37.23 45.98 0.96 0 Administration cost/ patient 186.15 37.23 35.79 Human resources [HR] Infliximab Adalimumab HR cost /min Time of administration process†[min] Total time [min] Total cost/ HR HR cost [min] Time of administration process†[min] Total time [min] Total cost/ HR Admission Supplying Patient preparation Medical examination Drug preparation Infusion Discharge Admission Supplying Patient preparation Medical examination Drug preparation Gastroenterologist 1.38 30 10 2 42 57.94 1.38 10 10 13.79 Nurse 0.44 1 10 10 120 141 62.04 0.44 2.27 10 12.27 5.40 Pharmacist 0.92 2 2 1.84 0.92 15 2.27 17.27 15.86 Administrative support 0.33 2 2 0.65 0.33 2.27 2.27 0.74 Total cost/phase 0.66 2.28 45.80 13.80 4.40 52.80 2.76 121.00 0.75 14.80 4.40 13.80 2.09 35.79 Materials consumed Unit cost Consumption Total consumption Total cost Unit cost Consumption Total consumption Total cost Infusion-chair 3.00 1 1 3.00 3.00 0 0 Infusion material cost‡ 16.44 1 1 16.44 14.94 0 Waste disposal hospital treated [ROT] [kg] 0.96 0.1 0.1 0.10 Overhead [20% of total amount] 37.23 45.98 0.96 0 Administration cost/ patient 186.15 37.23 35.79 *All costs are expressed in € [VAT included]; †per patient. ‡Saline, hydrophilic cotton, disinfectant solution, infusion bag, infusion set, lifecare pump, sterile plastic gloves, syringe and butterfly needle View Large 2.3. Statistical analysis Data were described using medians with interquartile ranges [IQRs] for continuous data, and percentages for discrete data. Baseline characteristics and TLs plus ITL assessments of patients from prospective and control groups were compared using t-tests, Mann–Whitney tests, χ2, and Fisher exact tests as appropriate. Correlations were explored using Spearman’s rank test. The proportion of patients with a clinical response 12 weeks after the therapeutic interventions in the TDM-based group was compared with that in the control group using the χ2 test and expressed as the absolute difference with 95% confidence intervals [CIs]. A p value of less than 0.05 was considered statistically significant. A one-way deterministic sensitivity analysis [OWSA] was conducted that considered the intrinsic variability of the data employed in the model.30 Such analysis involves a deterministic approach in which the model results fluctuate based on the variation of a given parameter at one time, according to changes reported in the literature or assumed by the authors. In this case, we excluded all cost drivers derived by the time-based ABC, such as the time spent by the professionals involved in the administration process, with variations that did not significantly impact the end results. We also performed a probabilistic sensitivity analysis [PSA], with 10 000 Monte-Carlo simulations, associating each category of variables considered in the economic model with their range of variability extrapolated from the literature or assumed by the clinicians. A cost-acceptance curve was developed to represent the results achieved in the PSA.31 In order to account for the uncertainty surrounding the value of the parameters included in both the one-way and the multiway sensitivity analyses, a standard deviation equal to 20% of the variable’s values was associated with each item. Furthermore, a normal distribution was associated with all the cost drivers monitored in the model, while clinical drivers were associated with a beta distribution [Table 4]. Analyses were performed with MedCalc Statistical Software, 9.2.1.0 [MedCalc software bvba, Ostende, Belgium] and Microsoft Excel with Visual Basic for Applications. Table 4. Parameters and distributions considered in the probabilistic sensitivity analysis [PSA]. Clinical drivers Base-case a b Min Max Distr. Treatment Prospective % Beta  Dose escalation IFX [%] 45% 0.79 0.97 18% 71%  Switch to other anti-TNFα [Adalimumab] [%] 25% 0.69 2.06 6% 39%  Other [%] 30% 0.75 1.74 9% 47%  Total 100% – – – – Other  Steroids 8% 0.28 3.34 0% 10%  Immunomodulators 42% 0.80 1.09 16% 66%  IFX withdrawal 15% 0.50 2.73 2% 23%  No treatment change [IFX 5MG] 8% 0.28 3.34 0% 10%  Surgery 12% 0.39 3.03 1% 17%  Other biologic drug 15% 0.50 2.73 2% 23% Cost drivers [IFX] Gastroenterologist Minutes  Patient preparation 30 – – 25.95 34.05 Normal  Medical examination 10 – – 8.65 11.35  Discharge 2 – – 1.73 2.27 Nurse  Drug provision 1 – – 0.87 1.13  Patient preparation 10 – – 8.65 11.35  Drug preparation 10 – – 8.65 11.35  Infusion 120 – – 103.81 136.19 Pharmacist  Drug provision 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 Cost drivers [ADA] Gastroenterologist  Medical examination 10 – – 8.65 11.35 Nurse  Drug provision 2 – – 1.73 2.27  Patient preparation 10 – – 8.65 11.35  Dispensation 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 Clinical drivers Base-case a b Min Max Distr. Treatment Prospective % Beta  Dose escalation IFX [%] 45% 0.79 0.97 18% 71%  Switch to other anti-TNFα [Adalimumab] [%] 25% 0.69 2.06 6% 39%  Other [%] 30% 0.75 1.74 9% 47%  Total 100% – – – – Other  Steroids 8% 0.28 3.34 0% 10%  Immunomodulators 42% 0.80 1.09 16% 66%  IFX withdrawal 15% 0.50 2.73 2% 23%  No treatment change [IFX 5MG] 8% 0.28 3.34 0% 10%  Surgery 12% 0.39 3.03 1% 17%  Other biologic drug 15% 0.50 2.73 2% 23% Cost drivers [IFX] Gastroenterologist Minutes  Patient preparation 30 – – 25.95 34.05 Normal  Medical examination 10 – – 8.65 11.35  Discharge 2 – – 1.73 2.27 Nurse  Drug provision 1 – – 0.87 1.13  Patient preparation 10 – – 8.65 11.35  Drug preparation 10 – – 8.65 11.35  Infusion 120 – – 103.81 136.19 Pharmacist  Drug provision 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 Cost drivers [ADA] Gastroenterologist  Medical examination 10 – – 8.65 11.35 Nurse  Drug provision 2 – – 1.73 2.27  Patient preparation 10 – – 8.65 11.35  Dispensation 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 View Large Table 4. Parameters and distributions considered in the probabilistic sensitivity analysis [PSA]. Clinical drivers Base-case a b Min Max Distr. Treatment Prospective % Beta  Dose escalation IFX [%] 45% 0.79 0.97 18% 71%  Switch to other anti-TNFα [Adalimumab] [%] 25% 0.69 2.06 6% 39%  Other [%] 30% 0.75 1.74 9% 47%  Total 100% – – – – Other  Steroids 8% 0.28 3.34 0% 10%  Immunomodulators 42% 0.80 1.09 16% 66%  IFX withdrawal 15% 0.50 2.73 2% 23%  No treatment change [IFX 5MG] 8% 0.28 3.34 0% 10%  Surgery 12% 0.39 3.03 1% 17%  Other biologic drug 15% 0.50 2.73 2% 23% Cost drivers [IFX] Gastroenterologist Minutes  Patient preparation 30 – – 25.95 34.05 Normal  Medical examination 10 – – 8.65 11.35  Discharge 2 – – 1.73 2.27 Nurse  Drug provision 1 – – 0.87 1.13  Patient preparation 10 – – 8.65 11.35  Drug preparation 10 – – 8.65 11.35  Infusion 120 – – 103.81 136.19 Pharmacist  Drug provision 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 Cost drivers [ADA] Gastroenterologist  Medical examination 10 – – 8.65 11.35 Nurse  Drug provision 2 – – 1.73 2.27  Patient preparation 10 – – 8.65 11.35  Dispensation 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 Clinical drivers Base-case a b Min Max Distr. Treatment Prospective % Beta  Dose escalation IFX [%] 45% 0.79 0.97 18% 71%  Switch to other anti-TNFα [Adalimumab] [%] 25% 0.69 2.06 6% 39%  Other [%] 30% 0.75 1.74 9% 47%  Total 100% – – – – Other  Steroids 8% 0.28 3.34 0% 10%  Immunomodulators 42% 0.80 1.09 16% 66%  IFX withdrawal 15% 0.50 2.73 2% 23%  No treatment change [IFX 5MG] 8% 0.28 3.34 0% 10%  Surgery 12% 0.39 3.03 1% 17%  Other biologic drug 15% 0.50 2.73 2% 23% Cost drivers [IFX] Gastroenterologist Minutes  Patient preparation 30 – – 25.95 34.05 Normal  Medical examination 10 – – 8.65 11.35  Discharge 2 – – 1.73 2.27 Nurse  Drug provision 1 – – 0.87 1.13  Patient preparation 10 – – 8.65 11.35  Drug preparation 10 – – 8.65 11.35  Infusion 120 – – 103.81 136.19 Pharmacist  Drug provision 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 Cost drivers [ADA] Gastroenterologist  Medical examination 10 – – 8.65 11.35 Nurse  Drug provision 2 – – 1.73 2.27  Patient preparation 10 – – 8.65 11.35  Dispensation 2 – – 1.73 2.27 Administrative support  Admission 2 – – 1.73 2.27 View Large 3. Results 3.1. Patients’ characteristics Ninety-six consecutive IBD [56 CD, 40 UC] patients who developed LoR to IFX were prospectively enrolled. Twelve patients were included from the paediatric centre [median age 15 years, range 6–17]. Fifty-two patients [28 CD, 24 UC] were included in the control group. The demographic and clinical characteristics of patients from both groups are shown in Table 5. No significant differences were found in terms of gender, age, type or extent of disease, dose or duration of IFX therapy, concomitant use of immunomodulators, or in the baseline CRP value between the two groups. However, a minority of patients [12%] were treated with IFX biosimilars in the prospective cohort. Table 5. Patients’ characteristics. Prospective cohort [n = 96] Control group [n = 52] p Crohn’s disease n [%] 56 [58] 28 [54] 0.60 Male n [%] 51 [53] 24 [46] 0.49 Age [years, mean, 95% CI] 38.9 [35.3–42.4] 42.7 [38.8–42.6] 0.18 Montreal classification A1; A2; A3 12; 35; 9 6; 18; 4 L1; L2; L3; p 12; 18; 26; 17 7; 11; 10; 10 B1; B2; B3 22; 25; 9 11; 14; 3 E1; E2; E3 5; 12; 23 0; 8; 16 Duration of IFX therapy [months, median, IQR] 17 [6.5–28.5] 17 [7–40] 0.63 Biosimilars n [%] 12 [12] 0 [0] 0.004 Immunomodulators n [%] 19 [20] 12 [23] 0.67 CRP mg/dL [median, IQR] 5 [2.9–7] 6.7 [3.3–9.5] 0.52 IFX trough levels [μg/mL] median [IQR] 1.7 [0.6–9.6] 3.4 [0.6–9.4] 0.08 Antibodies to IFX [ng/mL] median [IQR] 6.3 [2.7–13.9] 7 [4.3–25] 0.08 Prospective cohort [n = 96] Control group [n = 52] p Crohn’s disease n [%] 56 [58] 28 [54] 0.60 Male n [%] 51 [53] 24 [46] 0.49 Age [years, mean, 95% CI] 38.9 [35.3–42.4] 42.7 [38.8–42.6] 0.18 Montreal classification A1; A2; A3 12; 35; 9 6; 18; 4 L1; L2; L3; p 12; 18; 26; 17 7; 11; 10; 10 B1; B2; B3 22; 25; 9 11; 14; 3 E1; E2; E3 5; 12; 23 0; 8; 16 Duration of IFX therapy [months, median, IQR] 17 [6.5–28.5] 17 [7–40] 0.63 Biosimilars n [%] 12 [12] 0 [0] 0.004 Immunomodulators n [%] 19 [20] 12 [23] 0.67 CRP mg/dL [median, IQR] 5 [2.9–7] 6.7 [3.3–9.5] 0.52 IFX trough levels [μg/mL] median [IQR] 1.7 [0.6–9.6] 3.4 [0.6–9.4] 0.08 Antibodies to IFX [ng/mL] median [IQR] 6.3 [2.7–13.9] 7 [4.3–25] 0.08 View Large Table 5. Patients’ characteristics. Prospective cohort [n = 96] Control group [n = 52] p Crohn’s disease n [%] 56 [58] 28 [54] 0.60 Male n [%] 51 [53] 24 [46] 0.49 Age [years, mean, 95% CI] 38.9 [35.3–42.4] 42.7 [38.8–42.6] 0.18 Montreal classification A1; A2; A3 12; 35; 9 6; 18; 4 L1; L2; L3; p 12; 18; 26; 17 7; 11; 10; 10 B1; B2; B3 22; 25; 9 11; 14; 3 E1; E2; E3 5; 12; 23 0; 8; 16 Duration of IFX therapy [months, median, IQR] 17 [6.5–28.5] 17 [7–40] 0.63 Biosimilars n [%] 12 [12] 0 [0] 0.004 Immunomodulators n [%] 19 [20] 12 [23] 0.67 CRP mg/dL [median, IQR] 5 [2.9–7] 6.7 [3.3–9.5] 0.52 IFX trough levels [μg/mL] median [IQR] 1.7 [0.6–9.6] 3.4 [0.6–9.4] 0.08 Antibodies to IFX [ng/mL] median [IQR] 6.3 [2.7–13.9] 7 [4.3–25] 0.08 Prospective cohort [n = 96] Control group [n = 52] p Crohn’s disease n [%] 56 [58] 28 [54] 0.60 Male n [%] 51 [53] 24 [46] 0.49 Age [years, mean, 95% CI] 38.9 [35.3–42.4] 42.7 [38.8–42.6] 0.18 Montreal classification A1; A2; A3 12; 35; 9 6; 18; 4 L1; L2; L3; p 12; 18; 26; 17 7; 11; 10; 10 B1; B2; B3 22; 25; 9 11; 14; 3 E1; E2; E3 5; 12; 23 0; 8; 16 Duration of IFX therapy [months, median, IQR] 17 [6.5–28.5] 17 [7–40] 0.63 Biosimilars n [%] 12 [12] 0 [0] 0.004 Immunomodulators n [%] 19 [20] 12 [23] 0.67 CRP mg/dL [median, IQR] 5 [2.9–7] 6.7 [3.3–9.5] 0.52 IFX trough levels [μg/mL] median [IQR] 1.7 [0.6–9.6] 3.4 [0.6–9.4] 0.08 Antibodies to IFX [ng/mL] median [IQR] 6.3 [2.7–13.9] 7 [4.3–25] 0.08 View Large 3.2. ITL and ATI assessment and therapeutic interventions The median ITLs and ATI levels were comparable for the two groups [Table 5]. However, the baseline ITLs were numerically lower in the prospective cohort compared with in the control group [p = 0.08]. No relevant correlations were found between the ITLs or the ATIs with IBD type, sex, age, duration of therapy with IFX, concomitant use of immunomodulators, or CRP values at inclusion. There were no differences with respect to the distributions into the four groups of the algorithm [Table 6]. With regard to therapeutic interventions, the management of LoR significantly differed between the two groups. The rate of IFX dose escalation was significantly lower in the TDM-based group compared with in the control group [43/96, 45% vs 37/52, 71%, respectively; p = 0.003]. Conversely, a significantly greater percentage of patients switched to a second anti-TNFα in the TDM group [24/96, 25% in the TDM-based group vs 2/52, 4% in the control group; p = 0.001]. The two cohorts did not differ according to the use of other therapeutic interventions [p = 0.56] [Supplementary Materials Table 1]. There was a correspondence between the theoretical algorithm–based intervention and the performed therapeutic interventions in 63% of cases in the prospective cohort compared with 39% in the retrospective cohort [p = 0.00053]. Fifty-three percent of the escalations [23/43] were performed in concordance with the theoretical algorithm in the prospective cohort, compared with 24% [9/37] in the control group [p = 0.011] [Table 7]. Table 6. Distribution of patients into the groups of the therapeutic algorithm. Group Prospective cohort n [%] Control group n [%] p 1 28 [29] 14 [27] 0.84 2 36 [38] 19 [36.5] 1 3 28 [29] 13 [25] 0.70 4 4 [4] 6 [11.5] 0.17 Group Prospective cohort n [%] Control group n [%] p 1 28 [29] 14 [27] 0.84 2 36 [38] 19 [36.5] 1 3 28 [29] 13 [25] 0.70 4 4 [4] 6 [11.5] 0.17 View Large Table 6. Distribution of patients into the groups of the therapeutic algorithm. Group Prospective cohort n [%] Control group n [%] p 1 28 [29] 14 [27] 0.84 2 36 [38] 19 [36.5] 1 3 28 [29] 13 [25] 0.70 4 4 [4] 6 [11.5] 0.17 Group Prospective cohort n [%] Control group n [%] p 1 28 [29] 14 [27] 0.84 2 36 [38] 19 [36.5] 1 3 28 [29] 13 [25] 0.70 4 4 [4] 6 [11.5] 0.17 View Large Table 7. Therapeutic interventions and correspondence with the algorithm. Therapeutic interventions Prospective cohort n [%] Control group n [%] p Dose escalation 43 [45] 37 [71] 0.003 Switch to a 2nd anti-TNFα 24 [25] 2 [4] 0.001 Other 29 [30] 13 [25] 0.56 Total correspondence to algorithm 60 [63] 17 [39] 0.00053 Dose escalation in accordance with algorithm 23 [53] 9 [24] 0.011 Therapeutic interventions Prospective cohort n [%] Control group n [%] p Dose escalation 43 [45] 37 [71] 0.003 Switch to a 2nd anti-TNFα 24 [25] 2 [4] 0.001 Other 29 [30] 13 [25] 0.56 Total correspondence to algorithm 60 [63] 17 [39] 0.00053 Dose escalation in accordance with algorithm 23 [53] 9 [24] 0.011 View Large Table 7. Therapeutic interventions and correspondence with the algorithm. Therapeutic interventions Prospective cohort n [%] Control group n [%] p Dose escalation 43 [45] 37 [71] 0.003 Switch to a 2nd anti-TNFα 24 [25] 2 [4] 0.001 Other 29 [30] 13 [25] 0.56 Total correspondence to algorithm 60 [63] 17 [39] 0.00053 Dose escalation in accordance with algorithm 23 [53] 9 [24] 0.011 Therapeutic interventions Prospective cohort n [%] Control group n [%] p Dose escalation 43 [45] 37 [71] 0.003 Switch to a 2nd anti-TNFα 24 [25] 2 [4] 0.001 Other 29 [30] 13 [25] 0.56 Total correspondence to algorithm 60 [63] 17 [39] 0.00053 Dose escalation in accordance with algorithm 23 [53] 9 [24] 0.011 View Large 3.3. Clinical outcome Three patients in the prospective group did not complete the 12-week assessment because surgery was needed during the study interval. There was a clinical response 12 weeks from the therapeutic intervention in 52% [48/93, 95% CI 42–61%] of patients in the prospective group compared with 54% [28/52, 95% CI 40–67%] in the control group [p = 1]. No significant differences in terms of clinical response were found between the two groups, when patients were subdivided according to the clinical interventions adopted [Supplementary Materials Table 2]. 3.4. Cost analysis The analysis of the unit costs, calculated as the sum of the activity-based monitoring costs, administration costs, and drug costs over the 12-week investigation for each therapeutic intervention, showed that the IFX dose escalation was associated with greater resource costs. As far as the cost of treatments is concerned, the aforementioned results imply that at least 25% of the dose escalation in the retrospective cohort could have been avoided without any clinical repercussions. Thus, if the therapeutic interventions had been based on the theoretical algorithm for all 145 patients from both cohorts [excluding the three who did not complete the study], it would have allowed a saving of €128 648.13 [–15%, Table 8], namely, ~€887/patient over the 12 weeks of treatment. Furthermore, the savings determined in the analysis were higher than the costs for the administration of the TDM test. In fact, for the control group, the cost of IFX dose escalation, equal to €282 669.04, could have been reduced by 15% [€42 400.36], as the total cost for the TDM assay was €4160. When biosimilars of IFX were included in the analysis, in Scenario 1 [100% biosimilar] the percentage of the saving generated was reduced by 10% compared with the base case [15%] and equal to 5%; in Scenario 2 [50% originator, 50% biosimilar], the saving was reduced by 3% compared with the base case, lowering it to 12%. Table 8. Total cost/patient for each therapeutic intervention and the cost savings calculated as the difference between the total costs of the empirical and TDM approaches for a sample of 145 patients. Total cost/patient for each strategy Dose escalation 2nd anti-TNFα [adalimumab] Other Total cost [145 patients] Control group [%] 71% 4% 25% Cost empirical approach €7 639.70 €5 095.41 €1 588.73 €874 219.77 Prospective cohort [%] 45% 25% 30% Cost TDM approach €7 719.70 €5 175.41 €889.14 €745 571.64 Differential €128 648.13 Saving TDM 15% Total cost/patient for each strategy Dose escalation 2nd anti-TNFα [adalimumab] Other Total cost [145 patients] Control group [%] 71% 4% 25% Cost empirical approach €7 639.70 €5 095.41 €1 588.73 €874 219.77 Prospective cohort [%] 45% 25% 30% Cost TDM approach €7 719.70 €5 175.41 €889.14 €745 571.64 Differential €128 648.13 Saving TDM 15% View Large Table 8. Total cost/patient for each therapeutic intervention and the cost savings calculated as the difference between the total costs of the empirical and TDM approaches for a sample of 145 patients. Total cost/patient for each strategy Dose escalation 2nd anti-TNFα [adalimumab] Other Total cost [145 patients] Control group [%] 71% 4% 25% Cost empirical approach €7 639.70 €5 095.41 €1 588.73 €874 219.77 Prospective cohort [%] 45% 25% 30% Cost TDM approach €7 719.70 €5 175.41 €889.14 €745 571.64 Differential €128 648.13 Saving TDM 15% Total cost/patient for each strategy Dose escalation 2nd anti-TNFα [adalimumab] Other Total cost [145 patients] Control group [%] 71% 4% 25% Cost empirical approach €7 639.70 €5 095.41 €1 588.73 €874 219.77 Prospective cohort [%] 45% 25% 30% Cost TDM approach €7 719.70 €5 175.41 €889.14 €745 571.64 Differential €128 648.13 Saving TDM 15% View Large According to the deterministic sensitivity analysis, the main cost driver that affected the difference between the two approaches was the percentage of patients undergoing IFX dose escalation, since its increase resulted in an important decline in terms of savings. The same trend, with a less significant magnitude, was observed for an increase in the percentage of patients who switched to another anti-TNFα [adalimumab] [Figure 1]. The results of the PSA are shown in Figure 2. The curve has a steep slope and demonstrates that the introduction of the proposed algorithm in clinical practice generates savings and is likely to generate higher savings than those achieved in the base case [–15%]. In particular, the analysis shows a probability of >80% associated with the employment of the algorithm [compared with the standard care] of generating a >10% decrease in expenditure. Figure 1. View largeDownload slide One-way sensitivity analysis: IFX dose escalation vs TDM approach. Figure 1. View largeDownload slide One-way sensitivity analysis: IFX dose escalation vs TDM approach. Figure 2. View largeDownload slide Probabilistic savings curve: IFX dose escalation vs TDM approach. Figure 2. View largeDownload slide Probabilistic savings curve: IFX dose escalation vs TDM approach. In order to facilitate the comparability of the economic results achieved in the present analysis with those of other studies already realized in different settings, a threshold analysis was carried out in order to determine the price of IFX, concerning which the policy-maker is indifferent between the two therapeutic paths. In particular, the analysis showed that the price of IFX originator, which is 25% higher than the biosimilar version, would need to be reduced by >40% in order to make null the savings the TDM approach would guarantee. 4. Discussion The present study demonstrated that, for patients with LoR to IFX, an individualized management based on TDM was more cost-effective than an empirical IFX dose escalation in clinical practice. The TDM approach was based on a previously described algorithm,8 guiding physicians’ therapeutic interventions based on the ITL and ATI results. However, we adopted a higher threshold for detecting ITLs than the Danish trial [3 μg/mL vs 0.5 μg/mL, respectively], to limit the mislabelling of patients. Accordingly, patients with ITLs of ≥0.5 and ≤3 μg/mL, without ATIs, were suitable for an IFX dose escalation, rather than a change in the anti-TNFα class, which may lead to mechanistic failure [up to 70%].8,32 The percentage of patients who received therapeutic interventions according to the theoretical algorithm was similar in our study and in the Danish trial [63% versus 59%]. To our knowledge, our study is the first conducted in a clinical practice setting, with a prospective design and an a priori establishment of cut-offs for the ITLs and ATIs, that uses a therapeutic intervention algorithm and includes a control group. Three previous observational studies explored the role of TDM for managing anti-TNFα [both IFX and adalimumab] in secondary-failure patients.9,33,34 However, in these studies, patients were empirically managed, and the outcome of the clinical interventions was related a posteriori to the TLs of drugs and ADAs during LoR. Our study confirmed that the two strategies were equivalent in terms of the short-term clinical and biological responses. Recently, Kelly et al. retrospectively compared data from two cohorts of IFX-treated patients undergoing dose escalations at their centre: one group was TDM-guided and one was based on clinical data without TDM. After a median follow-up of 6 months, the authors observed a higher rate of endoscopic remission [63% vs 48%, p < 0.005] and clinical response [69% vs 57%, p < 0.001] and lower rate of hospitalization [22% vs 35%, p = 0.025] in the TDM group compared with in the empirical one.35 By our cost analysis, the TDM approach resulted in a significant cost savings, estimated at €128 648.13 [15%, Table 7, Supplementary Materials Figure 1] or ~€887/patient over the 12 weeks of treatment. The main cost driver was the percentage of patients undergoing IFX dose escalation, which was significantly higher in the empirical group [71% vs 45%, respectively, p = 0.003] and only partially necessary according to the algorithm [53% vs 24%, p = 0.011] [Table 7]. Interestingly, the baseline ITLs were numerically lower in the prospective cohort compared with in the empirical group, and this gap, although not significant, might have impacted on the difference in the proportions of patients having dose escalation. Recently Martelli et al.36 performed a systematic review comparing the cost-effectiveness of TDM vs the empirical approach for the management of IBD and rheumatoid arthritis [RA] patients treated with anti-TNFα. Seven studies were included: two randomized controlled trials on IBD8,37 and five studies using a modelling approach [Roblin et al. pers. comm., and four cited references].38–41 All the studies showed that the TDM strategy is more cost-effective than an empirical one in IBD and RA patients, with no negative impact on efficacy. The main limitation of our study was its non-randomized nature and the use of an historical population as a control group. Moreover, the major use of an IFX biosimilar [used by only 12% of patients from the prospective cohort] could significantly reduce the costs related to therapy. In relation to this, we simulated in two additional scenarios the use of an IFX biosimilar by 50% and 100% patients, and we still obtained significant savings by the use of TDM approach [–12% and –5%, respectively]. The cut-off values adopted in the present study were chosen according to the data available at the time of study design. However, a higher threshold for ITLs has recently been suggested.32 We then performed a subgroup analysis of Group 2 [patients with adequate ITLs and negative ADAs]. The median ITL of Group 2 patients was 7.4 μg/mL [IQR 5.6–10.9]: this value is higher than the recently defined cut-off of 5 μg/mL.32 Moreover, vedolizumab [VDZ] has only been commercially available in Italy for treating IBD patients since the second half of 2016. To date, VDZ is the first biologic, non-targeting TNF-α available and represents the best choice for patients who develop a mechanistic LoR [Group 2 in our cohort]. The inclusion of VDZ in our analysis could have significantly influenced the costs. Nevertheless, because the percentage of patients in Group 2 in both cohorts eligible for a switch to VDZ was similar [38% and 36%, Table 2], the impact on cost would have been comparable; thus, the optimization of IFX would remain the primary driver of the budget impact. Furthermore, in the empirical setting, the switch would probably be done after failing a period of IFX optimization, with increased costs. Our cost analysis included drug-related costs as well as the costs of specialist medical visits and of each material and resource [including human resources] for therapy administration and patient follow-up, according to current consumption. Our cost analysis, furthermore, was limited to medical treatments, as the three patients who underwent surgery were excluded from the evaluation. The two studied groups were recruited in different locations and over different time periods: this could have affected the results, although we recorded a good adherence to the study protocol in the prospectively recruited cohort. Finally, our study did not take into account the addition of an immunomodulator to the infliximab therapy. Some recent reports have suggested the utility of this strategy, in order to reduce ATIs and increase ITLs.42 A recently published consensus statement depicts a more complex scenario, in which ATI titres [low versus high] are considered and combination therapy with immunomodulators is advised in case of subtherapeutic ITLs and low ATIs.43 The cost-effectiveness of this approach should be addressed with an adequately powered study. With regard to ATI assay, we employed a drug-sensitive ELISA. By this method we found, in our populations, 86 patients [57 in the prospective group and 29 in the control group] with circulating IFX and ATI levels under the limit of detection or inconclusive. The usefulness of a drug-tolerant assay, as compared with a drug-sensitive one, has been extensively debated in recent years. However, the most recently published guidelines corroborate our approach, stating that there is insufficient evidence to recommend a drug-tolerant assay for anti-drug antibody detection.43 In conclusion, in a clinical practice setting, the TDM strategy for IFX secondary-failure patients was more cost-effective than an empirical approach, with similar clinical effectiveness. Therefore, physicians and health-care authorities should promote TDM in clinical practice, to best allocate the economic resources in the face of growing use of biologic therapies. The possibility of extending these conclusions to adalimumab or to other biologics cannot, however, be confirmed by extrapolating our data, and it should be addressed by appropriate research. Finally, given the observational nature of our study and the use of historical controls, these results should be replicated in a randomized prospective study that, at variance with the Danish trial,8 should include the recently defined ‘therapeutic’ cut-off values for ITLs. Supplementary Data Supplementary data are available at ECCO-JCC online. Funding The study was financed with grants from Catholic University of Sacred Heart, line D1, years 2013 and 2016. Conflict of Interest LG: Consultant for AbbVie, MSD, Mundipharma, Takeda; lecture fees from AbbVie, Janssen, MSD, Mundipharma, Takeda, Vifor Pharma, Zambon. DP: Lecture fees from AbbVie, MSD, Takeda. LC: Consultant for MSD. AA: Consultant for AbbVie, Allergan, Biogen, Celgene, Celltrion, Ferring, Hospira, Janssen, Lilly, MSD, Mundipharma, Pfizer, Samsung, Sofar, Takeda; Lecture fees from AbbVie, AstraZeneca, Chiesi, Ferring, Hospira, Janssen, MSD, Mitsubishi Tanabe, Mundipharma, Nikkiso, Pfizer, Otsuka, Takeda, Tigenix, Zambon; Research grants from MSD. The remaining authors have no conflict of interest to disclose. Author Contributions LG, DP, AA: Study concept, design and supervision, and guarantor of the article; LG, DP,TPT, BT, LC, PB, FC, LB, MM, CF, FC, FV, MC, AK: acquisition of data; LG, DP, TPT, AB, MB, MR: analysis and interpretation of data; LG, DP: drafting of the manuscript; AA, AG, GLR, EG: revision of the manuscript for important intellectual content. All authors approved the final version of the manuscript. References 1. Allez M , Karmiris K , Louis E , et al. 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For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

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Journal of Crohn's and ColitisOxford University Press

Published: Sep 1, 2018

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