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The economics of adalimumab for ulcerative colitis Expert Rev. Pharmacoecon. Outcomes Res. Early online, 1–5 (2015)

Feng Xie Department of Clinical Epidemiology and Biostatistics, McMaster University Hamilton, Room H306 Martha Wing, St. Joseph’s Healthcare Hamilton 50 Charlton Ave., E. Hamilton L8N 4A6, Canada Tel.: +1 905 522 1155; extn. 35808 Fax: +1 905 308 7212 [email protected]

Ulcerative colitis is a chronic inflammatory disease, characterized by diffuse mucosal inflammation in the colon. Adalimumab, as a TNF-a blocker, offers a safe and efficacious treatment option for patients with moderate to severe ulcerative colitis and refractory or intolerant to conventional medications; however, its cost–effectiveness profile has not yet been well established. Future economic evaluations should choose appropriate comparators in the context of target-reimbursement decision making and focus on cost–effectiveness over a long time horizon. KEYWORDS: adalimumab . cost–effectiveness . economics . infliximab . ulcerative colitis

The disease

Ulcerative colitis (UC) is one of the two main types of inflammatory bowel disease of unknown etiology [1]. It is characterized by mucosal inflammation which generally starts in the rectum and extends through the entire colon [1]. The prevalence of UC is high in developed countries, ranging from 156 cases per 100,000 people in the US [2] to 291 cases per 100,000 people in Finland [3]. Symptoms of UC include, depending on inflammation severity, bloody diarrhea, abdominal cramps and pain, fatigue and weight loss [1]. UC can be debilitating and sometimes lead to lifethreatening complications. Medical managements

The goal of medical treatments of UC is to reduce inflammation, induce and maintain clinical remission and improve quality of life [1]. Conventional medical treatments for UC mainly consist of 5-aminosalicylates and corticosteroids. Monoclonal antibodies against TNF-a are recently established treatment options. Infliximab is an intravenously administered TNF-a blocker specifically for patients with moderate to severe UC and refractory or intolerant to conventional medications [4]. Adalimumab is an alternative medication in the same class but administered subcutaneously. It has demonstrated safety and efficacy informahealthcare.com

10.1586/14737167.2015.1031113

in inducing and maintaining clinical remission in the same patient population in randomized clinical trials (RCTs) [5–9] and observational studies [10,11]. For adalimumab administered at 160/80 mg at week 0/2 and 40 mg every other week and with concurrent corticosteroids or immunosuppressants compared with placebo, the overall clinical remission rate was 16.5 versus 9.3% at week 8 and 17.3 versus 8.5% at week 52 [6]. For those with previous anti-TNF-a exposure, the clinical remission rate was 22.0% for adalimumab versus 12.4% for placebo and the corresponding rates for those without previous anti-TNF-a exposure were 10.2 versus 3.0% at week 52 [6]. Of those adalimumab treated who had clinical response at week 8, 30.9% had clinical remission at week 52 [7]. For patients with the same condition, who failed corticosteroids and/or immunosuppressants but were antiTNF-a naı¨ve, the clinical remission rate ranged from 27.5 to 29.5% at week 52 [9]. The clinical benefits with adalimumab were maintained for up to 4 years [12]. Adalimumab has recently been approved by the EMA and the US FDA for treating adult patients with moderate to severe, active UC and who have had an inadequate response to conventional medications including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine, or who are intolerant to or have medical contraindications for such treatments.

 2015 Informa UK Ltd

ISSN 1473-7167

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Drug Profile

Xie

An indirect comparison based on the evidence from the four pivotal RCTs (i.e., ACT 1 and 2 [4], ULTRA 1 [8] and ULTRA 2 [6]) found that infliximab was statistically more effective than adalimumab in inducing clinical remission at week 8 but both drugs had comparable efficacy at week 52 [13]. Stidham et al. performed a network meta-analysis to compare comparative efficacy of three anti-TNF-a treatments (i.e., adalimumab, infliximab and golimumab) in treating UC. Although all three medications were more effective than placebo but no one is clinically superior to the others [14]. The authors suggested that other factors including cost and patient preference should be taken into consideration when choosing an anti-TNF-a treatment [14]. There were a few small observational studies that also reported that adalimumab was well tolerated and appeared to be a clinically beneficial option for UC patients who had previously responded to infliximab but then lost response or became intolerant [15–19]. Colectomy

Although medical treatment is the basic management option for UC, some patients may eventually need a surgical intervention. Over a 10-year observation, the cumulative colectomy rate was 9.8% [20], but various factors might jointly contribute to the risk of colectomy [21]. The rate of colectomy is decreasing with the increasing use of anti-TNF-a treatments [22]. Costs & cost–effectiveness of adalimumab for UC

Adalimumab offers a new medical treatment option for refractory or difficult-to-treat UC patients but is also expensive. The evidence on cost or cost–effectiveness associated with using adalimumab for UC patients is rather limited. ‘Ulcerative colitis’ combined with ‘economic evaluation’, ‘cost’, ‘cost–effectiveness’ or ‘cost-utility’ were the search terms on PubMed in October 2014. There was one study on cost per remission analysis [23], whereas only two cost-utility analyses were identified with one as a full journal publication [24] and the other a conference abstract [25]. The methods and results of these three studies are summarized in TABLE 1 and discussed in detail below. Methodology highlights

Lofland et al. [23] conducted an analysis to estimate the medication cost per clinical remission for treating moderate to severe UC with adalimumab (drug acquisition cost only) versus infliximab (drug acquisition cost and infusion cost). The other two studies were cost-utility analyses [24,25]. Pivotal trials on adalimumab were commonly used as source RCTs in all three studies. Markov model was used to synthesize clinical and economic data in both full economic evaluations. The analysis was conducted from a managed care perspective [25], whereas the other two from the perspective of a public health care payer [23,24]. The time horizon was short varying from 54 weeks in the cost analysis [23] to 5 years in the full economic evaluations [24,25]. The cost analysis did not perform any incremental analysis or comparison [23]. Ali et al. [25] compared the cost– effectiveness of adalimumab versus standard care for moderate doi: 10.1586/14737167.2015.1031113

to severe UC but in an abstract presented at 2012 Annual Scientific Meeting of American College of Gastroenterology. Compared with usual care, Xie et al. [24] evaluated optimal treatment sequencing started with 5 mg/kg infliximab as the first-line treatment followed by either 10 mg/kg infliximab (the 5/10IFXADA strategy) or adalimumab (the 5IFXADA strategy) for non-responders. If medical treatments failed, patients underwent total colectomy with a one-stage ileal-pouch anal anastomosis [24]. The costs relevant to the treatments under comparison are presented in TABLE 1. Main findings & conclusions

Over the 5-year time horizon, Xie et al. [24] estimated that the incremental cost per quality-adjusted life-year (QALY) was CAD $358,088 and $575,540 for the 5IFXADA strategy and the 5/10IFXADA strategy compared with the usual care strategy, respectively [24]. It should be noted that this economic evaluation was conducted before the publications of the ULTRA trials. In the one way deterministic sensitivity analyses, the incremental ratio varied from $273,081 to $527,236 for the comparison between the 5IFXADA strategy and usual care, and from CAD $428,676 to $889,227 for the comparison between the 5/10IFXADA strategy and usual care. Probabilistic sensitivity analysis found that usual care was the most cost-effective treatment if the willingness to pay value (WTP) was less than CAD $140,000/QALY. The probability of 5IFXADA being cost-effective arose to 0.5 when the WTP increased to $400,000/QALY. This economic analysis revealed that the treatment sequencing with 5 mg/kg infliximab followed by either increasing dose or switching to adalimumab was not cost-effective compared with usual care in treating moderate to severe UC. Lofland et al. [23] reported that the costs per clinical remission for infliximab and adalimumab for bio-naı¨ve patients were estimated at CAD $42,086 and $79,558 at week 8, and $147,379 and $330,767, respectively, at week 54, respectively. If both bio-naı¨ve and bio-experienced patients were included, the cost per clinical remission increased to $113,812 at week 8 and to CAD $360,836 at week 54 for adalimumab (no bioexperienced patients were included in the trials on infliximab). The costs per sustained clinical remission for bio-naı¨ve patients were CAD $203,205 for infliximab and $682,873 for adalimumab at week 54 [23]. One way deterministic sensitivity analysis was conducted by varying the infliximab infusion cost from CAD $169 to $2793. As a result, the total cost per clinical remission varied from CAD $143,518 to $258,852, whereas the total cost per sustained clinical remission varied from CAD $197,881 to $356,902. The authors concluded that infliximab had lower costs per clinical remission and per sustained clinical remission than adalimumab in treating moderate to severe UC patients. Ali et al. [25] reported the incremental costs per QALY for adalimumab versus standard care were £96,733 and £22,087 over a 1- and 5-year time horizons, respectively. The probabilistic sensitivity analysis revealed that the probability of adalimumab being cost-effective was 0.686 and 0.956 at the WTP Expert Rev. Pharmacoecon. Outcomes Res.

The economics of adalimumab for UC

Drug Profile

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Table 1. Summary of the economic evaluation on adalimumab. Lofland et al.

Ali et al.

Xie et al.

Publication year

2013

2012

2009

Country

US

UK

Canada

Study type

Cost analysis

Cost-utility analysis

Cost-utility analysis

Markov model-based

Markov model-based

Study design Source trials

ACT1 [4] ULTRA 2 [6]

ULTRA 1 [8] ULTRA 2 [6] M10-223†

ACT1 [4] ACT2 [4]

Perspective

Managed care

UK National Health Service

Publicly funded health care system

Time horizon

54 weeks

1 and 5 years

5 years

Treatments under comparison

IFX (5 mg/kg for a weight of 80 kg at weeks 0, 2, 6 and every 8 weeks up to week 46) ADA (160/80 mg at week 0/2 and 40 mg every other week up to week 50)

ADA (160/80 mg at week 0/2 and 40 mg every other week up to week 52) Standard care†

5 mg/kg IFX -> ADA (160/80/40 mg); 5 mg/kg IFX -> 10 mg/kg IFX -> ADA (160/80/40 mg); Usual care‡

Costs

Medication: IFX: $773.97 per 100 mg vial ADA: $1024.31 per 40 mg injection Infusion (IFX only): $257 per infusion

Medication†, medical services†, and surgery† (in 2010 British Pounds Sterling)

Medications costs: IFX 100 mg/vial $952 ADA 400 mg $715 Medical exam: $77 IPAA: $12,738 Surgical complications: $9304 (in 2008 Canadian dollars)

Outcome

NA

QALY

QALY

Base-case results

Cost per clinical remission at 54 weeks: ADA: $330,767 for bio-naı¨ve and $360,836 for all patients IFX: $147,379§; Cost per sustained clinical remission at 54 weeks: ADA: $682,873 and $698,393 for bio-naı¨ve and all patients, respectively IFX: $203,205§

The incremental costs per QALY gained for ADA vs standard care: £96,733 (1 year) and £22,087 (5 years); ADA dominant to surgery

The incremental costs per QALY $358,088 for 5IFXADA vs usual care and $575,540 for 5/10IFXADA vs usual care; the 5/10IFXADA was dominated by 5IFXADA

Deterministic sensitivity analysis

$143,518–$356,902 for IFX at 54 weeks (varying the IFX infusion cost only)

£18,933–£30,292 (5-year time horizon)

$273,081–$527,236 (5IFXADA vs usual care) $428,676–$889,227 (5/10IFXADA vs usual care)

Probabilistic sensitivity analysis

None

ADA 68.6% if WTP at £30,000/ QALY; 95.6% if WTP at £50,000/QALY

Usual care: 100% if the WTP

The economics of adalimumab for ulcerative colitis.

Ulcerative colitis is a chronic inflammatory disease, characterized by diffuse mucosal inflammation in the colon. Adalimumab, as a TNF-α blocker, offe...
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