Evaluating cost per remission and cost of serious adverse events of advanced therapies for ulcerative colitis | BMC Gastroenterology

Model structure

An analytic model was developed to estimate cost per response, cost per remission, and costs associated with managing SAEs and SIs for advanced therapies approved for the treatment of UC in the US. The comparators included intravenous (IV) vedolizumab [9], IV infliximab [10], oral tofacitinib (2 different maintenance regimens) [11], subcutaneous (SC) adalimumab [12], SC ustekinumab [13], and SC golimumab [14]. Induction regimens for the comparators were IV vedolizumab 300 mg at 0, 2, and 6 weeks, IV infliximab 5 mg/kg at 0, 2, and 6 weeks, oral tofacitinib 10 mg twice daily for at least 8 weeks, SC adalimumab 40 mg (4 injections in 1 day or 2 injections per day for 2 consecutive days), IV ustekinumab single dose using weight-based dosing (260 mg for up to 55 kg, 390 mg for > 55 kg to 85 kg, 520 mg for > 85 kg), and SC golimumab 200 mg at week 0, followed by 100 mg at 2 weeks. Maintenance regimens for the comparators were IV vedolizumab 300 mg every 8 weeks (Q8W), IV infliximab 5 mg/kg Q8W, oral tofacitinib 5 or 10 mg twice daily, SC adalimumab 40 mg every 2 weeks, SC ustekinumab 90 mg Q8W, and SC golimumab 100 mg every 4 weeks. The base case was defined as the drug acquisition cost and reimbursable cost (as determined from the Medicare limit file) for infusion/hour for drugs that are infused, and did not include added costs for administration services. The base case analysis assumed the comparators were administered according to their respective FDA-approved dosing regimens. The population contains a mixture of those who are anti–tumor necrosis factor (TNF) naïve and anti-TNF experienced, reflective of patients from the pivotal trials [5]. Cost per response, cost per remission, and costs on the management of SAEs and SIs were estimated over a 52-week time period. Induction and maintenance periods were calculated respectively and then combined.

Model inputs

Comparative efficacy and safety inputs were derived from a previously published network meta-analysis of pivotal trials [5]. Numbers needed to treat (NNT) for response and remission from the network meta-analysis were used to estimate drug costs associated with achieving the respective outcomes at 52 weeks. Clinical response was defined based on complete Mayo scores (which assess stool frequency, rectal bleeding, physician’s global assessment, and endoscopic findings) and partial Mayo scores (which omit the endoscopic findings). Except for VARSITY, all studies defined clinical response as a reduction in complete Mayo score of ≥ 3 points and ≥ 30% from baseline with an accompanying decrease in rectal bleeding subscore of ≥ 1 point or absolute rectal bleeding subscore of ≤ 1 point, and clinical remission as a complete Mayo score of ≤ 2 points and no individual subscore > 1 point. In VARSITY, endoscopy was not performed at week 6. Therefore, for the purpose of these analyses, clinical response in VARSITY was defined as a partial Mayo score reduction of ≥ 2 points and ≥ 25% from baseline with an accompanying decrease in rectal bleeding subscore of ≥ 1 point or absolute rectal bleeding subscore of ≤ 1 point, and remission as a partial Mayo score of ≤ 2 points and no individual subscore > 1 point. Clinical response at 52 weeks was available based on partial and complete Mayo scores from VARSITY, and because these numbers were similar (vedolizumab vs adalimumab relative risk based on complete and partial Mayo scores were 1.28 and 1.22, respectively), it was deemed appropriate to proceed with the inclusion of VARSITY within the efficacy analysis based on partial Mayo score. All clinical response and remission definitions were used during the induction period (6, 8, or 10 weeks) and maintenance period (52, 54, or 60 weeks), as determined by the clinical trials [5]. To provide consistent clinical response and/or remission estimates of all studies, the network meta-analysis adjusted for differing study designs (eg, treat-through vs rerandomization) by converting maintenance clinical response and remission among induction starters for treat-through trials to maintenance response and remission among responders at the start of maintenance [5]. Wholesale acquisition cost (WAC), accessed April 8, 2021, from REDBOOK [16], was used to calculate costs of induction and maintenance regimens for labeled dosing (Table 1). WAC represents the publicly available list price for a drug and does not include rebates or discounts.

Table 1 Annual cost per advanced therapy regimena (WAC)

Numbers needed to harm (NNH) for SAEs and SIs were used to estimate the healthcare costs associated with managing the respective safety-related outcomes associated with each advanced therapy. SAEs and SIs in this analysis represent SAEs and SIs that were mutually reported in the clinical trials and included in the network meta-analysis (acute hypersensitivity reaction, severe skin reactions, unspecified B-cell lymphoma, and inpatient-treated infection [including tuberculosis and opportunistic infections]).

Model calculations

The network meta-analysis model standardized the maintenance response and remission outcomes between studies categorically as no response, response but no remission, and remission [5]. Cost per outcome (response or remission) was calculated for each advanced therapy by multiplying the NNT with the cost of the respective drug regimen. For example, a therapy that costs $50,000/year and has a 52-week NNT for a remission score of 5 would result in a cost per remission of $250,000. Five patients would have to be treated for 1 patient to achieve and maintain remission at 52 weeks. Costs of drug regimens and efficacy rates differ during the induction and maintenance periods and were calculated independently before combining periods. Patients who were treated but did not respond during the induction period incurred induction costs but did not progress to maintenance therapy on the respective drugs.

Costs per SAE and SI per patient were calculated for each comparator by dividing the cost of the adverse event by the advanced therapy’s NNH (eg, an inpatient’s treated infection costs $10,774 and a therapy with an NNH for serious infection score of 10 would result in an additional $1077 per patient for that therapy compared with the reference). Vedolizumab was used as the reference drug for safety-related costs because its SAE rate was numerically the lowest in the network meta-analysis, though no statistically significant differences were observed [5]. The costs for treating the respective safety outcomes were derived from the Healthcare Cost and Utilization Project [17] and represent the average reimbursable hospital costs to treat the respective AEs (eg, costs of medication, personnel, equipment, services), weighted by the risk of each respective safety outcome (Table 2). Example calculations for costs per response and costs per SAE and SI are shown in Fig. 1.

Table 2 Mean weighted costs for adverse events and serious infections
Fig. 1

Example calculations of costs per responder and costs per SAE. AE adverse event, NNH number needed to harm, NNT number needed to treat, SAE serious AE

Sensitivity analyses

Two sensitivity analyses were performed to investigate the impact of dose escalation and site-of-care on cost per outcome. A systematic literature review, following the PRISMA guidelines [18], was performed in PubMed to identify published literature illustrating dose-escalation and site-of-care inputs (see Additional file 1: Fig. S1, systematic literature review search terms and PRISMA diagrams). There were 207 sources identified using search terms for “dose escalation” and 326 sources using search terms for “site-of-care.” Subsequent title, abstract, and full text review by the authors resulted in 3 appropriate sources for dose escalation and 2 appropriate sources for site-of-care. Authors reviewed the appropriate sources and collectively decided on 1 source for each of the sensitivity analyses based on the strength of the evidence and appropriateness of the endpoints investigated.

A sensitivity analysis was performed to examine dose escalation of vedolizumab, adalimumab, ustekinumab, golimumab, and infliximab [5, 19]. Dose escalation was defined as either a decrease in dosing interval or an increase in administered dose. Results revealing the prevalence of dose escalation along with the magnitude of dose escalation were used to calculate the overall increase in drug consumption for each advanced therapy. Observational evidence identified in the systematic literature review reports an increase in consumption above labeled dose of 14% for vedolizumab, 28% each for infliximab and ustekinumab, 16% for adalimumab, and 6% for golimumab. Infliximab had the highest prevalence of dose escalation and ustekinumab had the highest increase in dose (see Additional file 1: Table S1, dose escalation estimates).

An additional sensitivity analysis examined costs associated with site-of-care. The cost of IV-infused advanced therapies (vedolizumab and infliximab) are different based on the site where they are infused (physician office vs home infusion vs outpatient hospital) [20]. For example, it has been shown that costs related to outpatient hospital infusions are about 74%–84% more expensive than those for home infusions [20]. Observational evidence identified in the systematic literature review reported that the proportion of administrations that occurred in a physician’s office, at home, and in an outpatient hospital setting were 51.3%, 9.0%, and 39.7%, respectively, for vedolizumab, and 55.7%, 6.1%, and 38.2%, respectively, for infliximab [20]. The costs at each site-of-care were also reported [14] and can be found in Additional file 1: Table S2, which lists costs per infusion by site-of-care.

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