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Review
Biological therapies in Crohn’s disease: are they cost-effective? A critical appraisal of model-based analyses Expert Rev. Pharmacoecon. Outcomes Res. 14(6), 815–824 (2014)
Monia Marchetti1 and Nicola Lucio Liberato*2 1 Hematology Unit, Azienda Sanitaria Locale, Ospedale “Cardinal Massaia”, Asti, Italy 2 Department of Medicine, Azienda Ospedaliera della Provincia di Pavia, Ospedale “Carlo Mira”, Casorate Primo (PV), Italy *Author for correspondence: Tel.: +39 029 004 0224 Fax: +39 029 004 0304 [email protected]
In refractory Crohn’s disease, anti-TNF and anti-a 4 integrin agents are used for ameliorating disease activity but impose high costs to health-care systems. The authors systematically reviewed cost–effectiveness analyses based on decision models: most of the studies were judged to have a good quality, but a large portion assessed health and costs in a short time horizon, usually disregarding fistulizing disease and not considering safety. Infliximab induction followed by on-demand retreatment consistently proved to have a good cost per quality-adjusted life year, while maintenance treatment never satisfied commonly accepted cost-utility thresholds. Challenges in cost–effectiveness analysis include the lack of a standard model structure, a large variability in the costs of surgery and poor data on indirect costs. As clinical practice is moving to mucosal healing as a robust response marker, personalized schedules of anti-TNF therapies might prove cost-effective even in the perspective of the health-care system in the near future. KEYWORDS: cost–effectiveness analysis • crohn’s disease • decision analysis • health economics • inflammatory bowel disease
adopted for higher-risk patients in order to prevent complications.
Management of Crohn’s disease
Crohn’s disease (CD) is a chronic inflammatory bowel disease resulting from inappropriate immune responses to gut microbiota in genetically susceptible individuals. Inflammation, mainly mediated by TNF-a, is characterized by a relapsing-remitting behavior, involves all layers of the gut wall and potentially affects all gastrointestinal tracts. The clinical management of CD is so complex that several gaps in clinical evidence can be shown [1], in particular regarding comparisons among treatment strategies (step-up vs top-down treatment and head-to-head comparisons within and between treatment classes) and outcomes (mucosal healing, patientreported symptoms, remission beyond 2 years). Since guidelines recommend personalized treatments [2–4], a top-down approach including anti-TNF therapies is increasingly being informahealthcare.com
10.1586/14737167.2014.957682
Efficacy & safety of anti-TNF agents
Infliximab, adalimumab and certolizumab are effective as both induction and maintenance therapy in adult patients with moderate-tosevere CD, including patients with fistulas. The relative risk of maintenance of remission with anti-TNF agents versus placebo was 1.90 at week 4 (95% CI: 1.55–2.33) and 2.75 at weeks 48–56 (95% CI: 2.13–3.54) [5], that is, 16 fewer failures in 100 treated patients [2]. Anti-TNF agents were also superior to the placebo in inducing a complete response, that is, reduction of CDAI score by 70 points at week 4, and in achieving complete response 100, that is, reduction of CDAI score by 100 points during long-term maintenance. When compared with placebo, anti-TNF therapy was associated with 227 fewer relapses per 100 patients [6]. Finally,
2014 Informa UK Ltd
ISSN 1473-7167
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Potentially relevant studies identified through databases search (n = 80)
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Studies excluded (n = 64) • Not based on a decision model (n = 4) • Dealing with health-care resources alone (n = 45) • Reviews (n = 15)
Studies retained (n = 16)
Studies added, derived from web search (n = 2)
Studies included in the systematic review (n = 18)
interventions [14]. Therefore, several attempts have been made in different countries to assess the net impact of such drugs onto healthcare costs and patients’ health. Systematic review method
We searched MEDLINE, EMBASE, Cinhal and the Cochrane Library Health Economics Evaluation Database according to the queries reported by previously published systematic reviews [15,16]. We limited the search to English-language papers, retrieving 81 items. We further selected those papers adopting a decision model and excluded studies that did not compare treatments as well as those studies not assessing the monetary value of healthcare consequences of CD and treatments. Thus, we retrieved 16 papers (FIGURE 1). We further searched the NICE website and the whole web for technology assessments that had not published by medical journals and retrieved two reports from NICE and one from the Canadian Coordinating Office for Health Technology Assessment: we selected only the latest of the two NICE assessments. Retrieved studies overlapped with those reported by a recent systematic review [16].
Figure 1. Flow chart of the systematic literature review.
anti-TNF agents were also superior to the placebo in fistula healing. Although the risk of significant side effects, in particular opportunistic infections, has been claimed, a recent metaanalysis proved that the safety profile of anti-TNF therapy was not significantly different from placebo [5]. These results were confirmed by two further meta-analyses: the proportion of patients with severe adverse events was lower with TNF-a inhibitors than with placebo (OR: 0.80; 95% CI: 0.67–0.96; p = 0.01) [7] and not significantly different after maintenance therapy [6]. The risks of malignancy and serious infection were found not significantly increased (p > 0.05) [6,7]. A note of caution remains on opportunistic infections [8]. In steroid-refractory CD patients, azathioprine is a more realistic comparator for TNF-a inhibitors; however, infliximab, either alone or associated with azathioprine, reduced 15–27 failures of remission when compared with azathioprine alone, respectively [6]. Further monoclonal antibodies recently reported to be effective in this setting are certolizumab, vedolizumab and natalizumab, the latter both targeted against a4-integrin, although with a different molecular mechanism [9–11]. Economic issues
CD has a clinical fluctuating course with period of remission alternating with relapses that often induce hospitalizations which are responsible for two-thirds of the overall healthcare costs for CD, that is, e16.7 billion per year in Europe [12]. Moreover, indirect costs, such as lost of productivity due to unemployment and missed days of work of patients and caregivers, represent up to twice the direct healthcare costs [13]. The introduction of anti-TNF agents induced an increase of healthcare expenses for drug therapy of patients with CD, but also proved to reduce hospitalizations and surgical 816
Critical appraisal method We chose two checklists for the systematic assessment of health economic studies that were endorsed respectively by European Network of Health Economics Evaluation Database (EURONHEED) [17] and by ISPOR (Consolidated Health Economic Evaluation Reporting Standards) [18]. The former checklist, as modified by Gaultney et al., consists of 15 items to which we assigned ‘yes’ or ‘no’ scores [19]. The latter consists of 26 items: to each item we assigned a score of 0 if the item was completely unmet, 1 if it was partially met and 2 if it was fully accomplished. The two authors independently applied the checklists to the 18 selected papers. Inconsistent scores were resolved by face-to-face discussion. Results General issues
Most of the studies were published quite recently, that is, 78% in the last 8 years, usually in the USA or the UK, where pharmacoeconomics has a major regulatory role (TABLES 1 & 2). Onethird of the reports were issued by a specialty journal, while slightly less than half were issued by nonclinical journals. Therefore, gastroenterologists, usually accessing clinical journals, could have the opportunity to face cost–effectiveness evaluations of anti-TNF drugs in only a few occasions. Patients and treatments
Most of the studies modeled patients with luminal CD: only three studies addressed fistulizing CD (TABLE 1). and one was devoted to postsurgical medical treatment [20]. Modeled patients ranged from children [21] to 45-year-old adults [22]: average modeled age ranged from 30 to 38 in six studies, but it was not declared in most studies. Only two studies were devoted or included pediatric patients [15,21]. Modeled patient weight ranged from 60 to 73 kg, but it was reported only by eight studies (TABLE 2). Expert Rev. Pharmacoecon. Outcomes Res. 14(6), (2014)
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[31]
22 7 Standard care
35
[25]
34 11
7 I, M
†
Standard care
[28]
36 9 Certolizumab, natalizumab
Infliximab therapy without azathioprin. D: On-demand therapy; (de): Dose escalation; I: Induction therapy; M: Maintenance therapy.
I, M No Yes Japan Saito et al. (2014)
†
I, M No UK Saito et al. (2013)
No
Italy Marchetti et al. (2013)
No
No
I, D
I, M I, M No USA Tang et al. (2012)
No
[30]
39 12 No Canada Blackhouse et al. (2012)
Yes
USA Ananthakrishnan et al. (2012)
No
No
I, M
I, M, D No UK Dretzke et al. (2011)
No
I, M No USA Ananthakrishnan et al. (2011)
Yes
UK Punekar et al. (2010)
No
No
I, M
I, M
Standard care
[27]
24 8 Certolizumab, natalizumab
[15]
39 10 Standard care
[20]
19 9 Standard care, no treatment
[21]
36 Standard care
I, M I, M No USA Yu et al. (2009)
No
No USA Loftus et al. (2009)
Yes
7
[45]
38 9
[46]
30 10 Standard care I, M
[47]
35 11 I, M I, M No UK Bodger et al. (2009)
Yes
UK Lindsay et al. (2008)
Yes
Yes
I, M
I I (de) No USA Kaplan et al. (2007)
Yes
I, M, D No France Jaisson-Hot et al. (2004)
No
I, M,D Yes UK Clark et al. (2003)
No
I, M, D No Ontario Marshall et al. (2002)
No
I, D Yes USA Arsenau et al. (2001)
Yes
Standard care
[22]
43 Standard care
9
[29]
25 9
[24]
15 Standard care
8
[57]
24 8
[26]
41 10 Standard care
[23]
41 9 Standard care
Ref. ISPOR score EURONHEED score Comparing/ other strategies Adalimumab Infliximab Clinical journal Country Study (year)
Eleven studies adopted a Markov model. The number of modeled nonadsorbing health states ranged from 3 to 8 (TABLE 3), but four states were shared by all the models: active disease, medical remission, surgery and postsurgery remission. ‘Remission’ is defined as a CDAI score lower than 150 and ‘medical remission’ represents patients with a CDAI score 1 year.
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Well-defined research question
100%
Comprehensive description of the competing alternatives
33%
Effectiveness of the programmes or services established
67%
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All relevent costs/consequences for each alternative identified
44%
Appropriate units for measurements of costs and consequences
83%
Creadible valuation of costs and conseqences
83%
Adjustement for differential timing
44%
Incremental analysis performed
100% 94%
Assessment of uncertainty Conclusion easily interpretable and based on comparison
100%
Comparison of results with previous studies Discussion of generalizability
61% 17%
Discussion of important factors to be taken into account Discussion of issues of implementation
67% 17%
Figure 2. Proportion of studies satisfying European Network of Health Economics Evaluation Database criteria.
adalimumab versus infliximab of more than £50M/QALY [15] and US$2.4M/QALY [28]. Certolizumab was compared versus natalizumab in one study but proved similar effectiveness, while natalizumab induced higher costs [27]. A few studies assessed the budget impact of biological therapies [15,25]. One-way sensitivity analyses performed in the different studies could not trace critical factors except disease severity, drug cost, the cost of surgery and time horizon. Study quality
Quality score ranged from 7 to 13 (median 9) in EURONHEED scale and from 15 to 43 (median 35) in ISPOR scale (FIGURES 2 & 3, TABLE 1). Four EURONHEED items and 13 ISPOR items were fulfilled by over 90% of the studies. Onethird of ISPOR quality items were at least partially fulfilled by all the studies. Correlation coefficient between the two scores was 0.41. No different quality was observed in studies conducted in the USA or the UK setting, or in studies published after 2010. Studies published in clinical journals did not show inferior quality to those published in health economic journals or technology assessments. Those studies performing secondorder sensitivity analysis, acceptability curve or Monte Carlo plots were assigned significantly higher median quality score (8.5 vs 9.5 EURONHEED scores; 24 vs 37 ISPOR scores). Most of the studies lacked a comprehensive view of all possible alternative strategies and clinical subgroups. Currency adjustment methods were rarely reported, as well as full range and distributions of input parameters. Moreover, introduction and discussion rarely faced implementation and generalizability as well as opportunity costs. Rarely a full comparison with previously published cost utility analyses was discussed. Expert commentary
Infliximab or adalimumab therapy followed by mid-term maintenance therapy for 1 or 2 years and subsequent shift to 820
another anti-TNF agent in case of failure can be cost-effective compared with nonbiological therapy in a long-term time horizon and a societal perspective, in the most appropriate clinical setting, that is, severe luminal disease or pediatric patients. Inconsistent results from different studies can be explained by different time horizons or different estimations of data missing from the literature, such as hospitalization rates. Moreover, heterogenous data sources for efficacy can also explain the results: head-to-head studies comparing different biological therapies are lacking as well as crossover studies. Timeframe of the analysis is critical because patients showed to be highly risk-averse [48]. Finally, real-life management of CD includes dose adjustments with dose escalations, as well as, on the opposite, noncompliance to the treatment plan. Productivity loss due to CD is relevant since the disease is usually diagnosed in the second or third decade of life: indirect costs account for 28% in the USA to nearly 69% in Europe of overall disease-related costs [49]. Amelioration of disease activity correlates positively with patient productivity and decreases indirect costs by about US$10,000 per year [50]. Despite international guidelines for pharmacoeconomic evaluations recommending a societal perspective for the analyses, only one of the retrieved study considered indirect costs. Budget silos usually make societal evaluations less appealing to healthcare decision-makers. Five-year view
The future CD management involves an outcomes-based approach supporting the choice among different treatment strategies based on clinical data at presentation but also on biological remission. Therefore, symptoms-based decisions will be replaced by decisions based on endoscopic healing [51–53]; however, the exact degree of mucosal healing that will lead to improved long-term remission, decreased hospital and surgical rates remains unknown. A ‘treat to target’ strategy based on regular assessment of disease activity by objective measures and Expert Rev. Pharmacoecon. Outcomes Res. 14(6), (2014)
Review
Biologic therapies in CD
Score 2 Score 1 or 2 56% 89%
Title specific for economic evaluation and listing compared options 33%
83%
Abstract including perspective, setting,input data, uncertainty analysis
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22%
100%
Introduction starting the decision making context 28% Target population and subgroups: full description and account
100% 28%
89%
Description of setting and location of the decision 67% Study perspective and related cost issues
100% 61%
100%
Compared strategie: full description and account 33%
100%
Time horizon stated 33%
83%
Discount rate reported and discussed 22%
89%
Outcomes described and relevance discussed 61%
94%
Single study-based effectiveness data: full description of the study 17%
94%
Synthesis-based effectiveness data: full description of methods 56%
94%
Preference-based outcomes: details of sources 39%
94%
Single study-based resource use and costs: full description 44%
83%
Model-based resource use and costs: full description 39% 67%
Currency: stated methods for adjustment to the year of reported cost 28%
78%
Model description (graphic) and account 17%
94%
Analythic methods for input data management 22%
78%
Study parameters: full description (incl range and probability distribution) 11%
89%
Incremental outcomes 61%
First-order uncertainty characterization (incl discount and perspective) 28%
100% 94%
Second-order uncertainty characterization (incl model structure and assumptions) 33% Subgroup and scenario analyses
100% 44%
100%
Limitations and generalizability of the results discussed Funding and support declared Conflict of interest described
78% 83% 67% 83%
Figure 3. Proportion of studies satisfying ISPOR criteria.
subsequent adjustment of treatments is a new paradigm for CD management [54,55]. We wish that central regulatory agencies, that is, EMA and FDA, provide general shared recommendations on standards for modeling in drug authorization submissions and academic studies. We expect that homogeneous definition of health informahealthcare.com
states, input data, relevant intermediate end points, study perspective and time horizon would improve comparability and generalizability of health economic assessments. Health economic dossiers would be submitted to decision-makers in the different countries in a very shorter time and decisions would be much more transparent. 821
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Willingness to pay for one QALY varies across countries and usually vary according to disease severity. Therefore, commonly adopted cost–effectiveness thresholds might not be justified for severe disabling diseases incurring in working-age people, like CD. Moreover, single rare diseases impose a lower burden onto healthcare budget of industrialized countries. Therefore, commonly adopted standard ICUR threshold might not be fully justified either by equity or by health economics [56]. Indeed, infliximab maintenance therapy has been authorized for refractory nonfistulizing CD by most industrialized countries despite an ambiguous economic profile in the perspective of third-
party payers, without an explicit consideration of a societal perspective or acceptability thresholds specific for rare diseases. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Several effective biological therapies are available for Crohn’s disease (CD), but optimal scheduling and sequence has not been ascertained yet. • Monoclonal antibodies for CD provide quality-of-life amelioration at an acceptable cost for value if maintenance therapy is tailored, an appropriate time horizon is adopted and societal costs are considered. • Mucosal healing is a candidate intermediate end point for personalizing therapies for CD: future decision models should consider estimation of long-term outcomes based on such a parameter. • Standard model structure and main input parameters should be centrally defined in order to allow full comparability among modelbased cost–effectiveness studies.
therapy in inflammatory bowel disease. Dig Liver Dis 2011;43(1):1-20
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Bodger K, Kikuchi T, Hughes D. Cost-effectiveness of biological therapy for Crohn’s disease: Markov cohort analyses incorporating United Kingdom patient-level cost data. Aliment Pharmacol Ther 2009; 30(3):265-74 Waljee AK, Morris AM, Waljee JF, et al. Individual health discount rate in patients with ulcerative colitis. Inflamm Bowel Dis 2011;17(6):1328-32 Yu AP, Cabanilla LA, Wu EQ, et al. The costs of Crohn’s disease in the United States and other Western countries: a systematic
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53.
•
Geboes K, Rutgeerts P, Opdenakker G, et al. Endoscopic and histologic evidence of persistent mucosal healing and correlation with clinical improvement following sustained infliximab treatment for Crohn’s disease. Curr Med Res Opin 2005;21(11): 1741-54 Baert F, Moortgat L, Van Assche G, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn’s disease. Gastroenterology 2010; 138(2):463-8 The first study demonstrating the clinical relevance of mucosal healing.
54.
Bouguen G, Levesque BG, Feagan BG, et al. Treat to target: a proposed new paradigm for the management of Crohn’s disease. Clin Gastroenterol Hepatol 2013; doi; 10.1016/j.cgh.2013.09.006. [Epub ahead of print]
••
Up-to-date review on the new treatment paradigm in CD, that is, targeting therapy to mucosal healing.
55.
Bouguen G, Levesque BG, Pola S, et al. Endoscopic assessment and treating to target increase the likelihood of mucosal healing in patients with Crohn’s disease. Clin Gastroenterol Hepatol 2014;12(6):978-85
56.
Nord E, Johansen R. Concerns for severity in priority setting in health care: a review of trade-off data in preference studies and implications for societal willingness to pay for a QALY. Health Policy 2014;116(2-3): 281-8
57.
Clark W, Raftery J, Song F, et al. Systematic review and economic evaluation of the effectiveness of infliximab for the treatment of Crohn’s disease. Health Technol Assess 2003;7(3):1-77
Expert Rev. Pharmacoecon. Outcomes Res. 14(6), (2014)
Review
Biological therapies in Crohn’s disease: are they cost-effective? A critical appraisal of model-based analyses Expert Rev. Pharmacoecon. Outcomes Res. 14(6), 815–824 (2014)
Monia Marchetti1 and Nicola Lucio Liberato*2 1 Hematology Unit, Azienda Sanitaria Locale, Ospedale “Cardinal Massaia”, Asti, Italy 2 Department of Medicine, Azienda Ospedaliera della Provincia di Pavia, Ospedale “Carlo Mira”, Casorate Primo (PV), Italy *Author for correspondence: Tel.: +39 029 004 0224 Fax: +39 029 004 0304 [email protected]
In refractory Crohn’s disease, anti-TNF and anti-a 4 integrin agents are used for ameliorating disease activity but impose high costs to health-care systems. The authors systematically reviewed cost–effectiveness analyses based on decision models: most of the studies were judged to have a good quality, but a large portion assessed health and costs in a short time horizon, usually disregarding fistulizing disease and not considering safety. Infliximab induction followed by on-demand retreatment consistently proved to have a good cost per quality-adjusted life year, while maintenance treatment never satisfied commonly accepted cost-utility thresholds. Challenges in cost–effectiveness analysis include the lack of a standard model structure, a large variability in the costs of surgery and poor data on indirect costs. As clinical practice is moving to mucosal healing as a robust response marker, personalized schedules of anti-TNF therapies might prove cost-effective even in the perspective of the health-care system in the near future. KEYWORDS: cost–effectiveness analysis • crohn’s disease • decision analysis • health economics • inflammatory bowel disease
adopted for higher-risk patients in order to prevent complications.
Management of Crohn’s disease
Crohn’s disease (CD) is a chronic inflammatory bowel disease resulting from inappropriate immune responses to gut microbiota in genetically susceptible individuals. Inflammation, mainly mediated by TNF-a, is characterized by a relapsing-remitting behavior, involves all layers of the gut wall and potentially affects all gastrointestinal tracts. The clinical management of CD is so complex that several gaps in clinical evidence can be shown [1], in particular regarding comparisons among treatment strategies (step-up vs top-down treatment and head-to-head comparisons within and between treatment classes) and outcomes (mucosal healing, patientreported symptoms, remission beyond 2 years). Since guidelines recommend personalized treatments [2–4], a top-down approach including anti-TNF therapies is increasingly being informahealthcare.com
10.1586/14737167.2014.957682
Efficacy & safety of anti-TNF agents
Infliximab, adalimumab and certolizumab are effective as both induction and maintenance therapy in adult patients with moderate-tosevere CD, including patients with fistulas. The relative risk of maintenance of remission with anti-TNF agents versus placebo was 1.90 at week 4 (95% CI: 1.55–2.33) and 2.75 at weeks 48–56 (95% CI: 2.13–3.54) [5], that is, 16 fewer failures in 100 treated patients [2]. Anti-TNF agents were also superior to the placebo in inducing a complete response, that is, reduction of CDAI score by 70 points at week 4, and in achieving complete response 100, that is, reduction of CDAI score by 100 points during long-term maintenance. When compared with placebo, anti-TNF therapy was associated with 227 fewer relapses per 100 patients [6]. Finally,
2014 Informa UK Ltd
ISSN 1473-7167
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Potentially relevant studies identified through databases search (n = 80)
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Studies excluded (n = 64) • Not based on a decision model (n = 4) • Dealing with health-care resources alone (n = 45) • Reviews (n = 15)
Studies retained (n = 16)
Studies added, derived from web search (n = 2)
Studies included in the systematic review (n = 18)
interventions [14]. Therefore, several attempts have been made in different countries to assess the net impact of such drugs onto healthcare costs and patients’ health. Systematic review method
We searched MEDLINE, EMBASE, Cinhal and the Cochrane Library Health Economics Evaluation Database according to the queries reported by previously published systematic reviews [15,16]. We limited the search to English-language papers, retrieving 81 items. We further selected those papers adopting a decision model and excluded studies that did not compare treatments as well as those studies not assessing the monetary value of healthcare consequences of CD and treatments. Thus, we retrieved 16 papers (FIGURE 1). We further searched the NICE website and the whole web for technology assessments that had not published by medical journals and retrieved two reports from NICE and one from the Canadian Coordinating Office for Health Technology Assessment: we selected only the latest of the two NICE assessments. Retrieved studies overlapped with those reported by a recent systematic review [16].
Figure 1. Flow chart of the systematic literature review.
anti-TNF agents were also superior to the placebo in fistula healing. Although the risk of significant side effects, in particular opportunistic infections, has been claimed, a recent metaanalysis proved that the safety profile of anti-TNF therapy was not significantly different from placebo [5]. These results were confirmed by two further meta-analyses: the proportion of patients with severe adverse events was lower with TNF-a inhibitors than with placebo (OR: 0.80; 95% CI: 0.67–0.96; p = 0.01) [7] and not significantly different after maintenance therapy [6]. The risks of malignancy and serious infection were found not significantly increased (p > 0.05) [6,7]. A note of caution remains on opportunistic infections [8]. In steroid-refractory CD patients, azathioprine is a more realistic comparator for TNF-a inhibitors; however, infliximab, either alone or associated with azathioprine, reduced 15–27 failures of remission when compared with azathioprine alone, respectively [6]. Further monoclonal antibodies recently reported to be effective in this setting are certolizumab, vedolizumab and natalizumab, the latter both targeted against a4-integrin, although with a different molecular mechanism [9–11]. Economic issues
CD has a clinical fluctuating course with period of remission alternating with relapses that often induce hospitalizations which are responsible for two-thirds of the overall healthcare costs for CD, that is, e16.7 billion per year in Europe [12]. Moreover, indirect costs, such as lost of productivity due to unemployment and missed days of work of patients and caregivers, represent up to twice the direct healthcare costs [13]. The introduction of anti-TNF agents induced an increase of healthcare expenses for drug therapy of patients with CD, but also proved to reduce hospitalizations and surgical 816
Critical appraisal method We chose two checklists for the systematic assessment of health economic studies that were endorsed respectively by European Network of Health Economics Evaluation Database (EURONHEED) [17] and by ISPOR (Consolidated Health Economic Evaluation Reporting Standards) [18]. The former checklist, as modified by Gaultney et al., consists of 15 items to which we assigned ‘yes’ or ‘no’ scores [19]. The latter consists of 26 items: to each item we assigned a score of 0 if the item was completely unmet, 1 if it was partially met and 2 if it was fully accomplished. The two authors independently applied the checklists to the 18 selected papers. Inconsistent scores were resolved by face-to-face discussion. Results General issues
Most of the studies were published quite recently, that is, 78% in the last 8 years, usually in the USA or the UK, where pharmacoeconomics has a major regulatory role (TABLES 1 & 2). Onethird of the reports were issued by a specialty journal, while slightly less than half were issued by nonclinical journals. Therefore, gastroenterologists, usually accessing clinical journals, could have the opportunity to face cost–effectiveness evaluations of anti-TNF drugs in only a few occasions. Patients and treatments
Most of the studies modeled patients with luminal CD: only three studies addressed fistulizing CD (TABLE 1). and one was devoted to postsurgical medical treatment [20]. Modeled patients ranged from children [21] to 45-year-old adults [22]: average modeled age ranged from 30 to 38 in six studies, but it was not declared in most studies. Only two studies were devoted or included pediatric patients [15,21]. Modeled patient weight ranged from 60 to 73 kg, but it was reported only by eight studies (TABLE 2). Expert Rev. Pharmacoecon. Outcomes Res. 14(6), (2014)
informahealthcare.com
[31]
22 7 Standard care
35
[25]
34 11
7 I, M
†
Standard care
[28]
36 9 Certolizumab, natalizumab
Infliximab therapy without azathioprin. D: On-demand therapy; (de): Dose escalation; I: Induction therapy; M: Maintenance therapy.
I, M No Yes Japan Saito et al. (2014)
†
I, M No UK Saito et al. (2013)
No
Italy Marchetti et al. (2013)
No
No
I, D
I, M I, M No USA Tang et al. (2012)
No
[30]
39 12 No Canada Blackhouse et al. (2012)
Yes
USA Ananthakrishnan et al. (2012)
No
No
I, M
I, M, D No UK Dretzke et al. (2011)
No
I, M No USA Ananthakrishnan et al. (2011)
Yes
UK Punekar et al. (2010)
No
No
I, M
I, M
Standard care
[27]
24 8 Certolizumab, natalizumab
[15]
39 10 Standard care
[20]
19 9 Standard care, no treatment
[21]
36 Standard care
I, M I, M No USA Yu et al. (2009)
No
No USA Loftus et al. (2009)
Yes
7
[45]
38 9
[46]
30 10 Standard care I, M
[47]
35 11 I, M I, M No UK Bodger et al. (2009)
Yes
UK Lindsay et al. (2008)
Yes
Yes
I, M
I I (de) No USA Kaplan et al. (2007)
Yes
I, M, D No France Jaisson-Hot et al. (2004)
No
I, M,D Yes UK Clark et al. (2003)
No
I, M, D No Ontario Marshall et al. (2002)
No
I, D Yes USA Arsenau et al. (2001)
Yes
Standard care
[22]
43 Standard care
9
[29]
25 9
[24]
15 Standard care
8
[57]
24 8
[26]
41 10 Standard care
[23]
41 9 Standard care
Ref. ISPOR score EURONHEED score Comparing/ other strategies Adalimumab Infliximab Clinical journal Country Study (year)
Eleven studies adopted a Markov model. The number of modeled nonadsorbing health states ranged from 3 to 8 (TABLE 3), but four states were shared by all the models: active disease, medical remission, surgery and postsurgery remission. ‘Remission’ is defined as a CDAI score lower than 150 and ‘medical remission’ represents patients with a CDAI score 1 year.
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Well-defined research question
100%
Comprehensive description of the competing alternatives
33%
Effectiveness of the programmes or services established
67%
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All relevent costs/consequences for each alternative identified
44%
Appropriate units for measurements of costs and consequences
83%
Creadible valuation of costs and conseqences
83%
Adjustement for differential timing
44%
Incremental analysis performed
100% 94%
Assessment of uncertainty Conclusion easily interpretable and based on comparison
100%
Comparison of results with previous studies Discussion of generalizability
61% 17%
Discussion of important factors to be taken into account Discussion of issues of implementation
67% 17%
Figure 2. Proportion of studies satisfying European Network of Health Economics Evaluation Database criteria.
adalimumab versus infliximab of more than £50M/QALY [15] and US$2.4M/QALY [28]. Certolizumab was compared versus natalizumab in one study but proved similar effectiveness, while natalizumab induced higher costs [27]. A few studies assessed the budget impact of biological therapies [15,25]. One-way sensitivity analyses performed in the different studies could not trace critical factors except disease severity, drug cost, the cost of surgery and time horizon. Study quality
Quality score ranged from 7 to 13 (median 9) in EURONHEED scale and from 15 to 43 (median 35) in ISPOR scale (FIGURES 2 & 3, TABLE 1). Four EURONHEED items and 13 ISPOR items were fulfilled by over 90% of the studies. Onethird of ISPOR quality items were at least partially fulfilled by all the studies. Correlation coefficient between the two scores was 0.41. No different quality was observed in studies conducted in the USA or the UK setting, or in studies published after 2010. Studies published in clinical journals did not show inferior quality to those published in health economic journals or technology assessments. Those studies performing secondorder sensitivity analysis, acceptability curve or Monte Carlo plots were assigned significantly higher median quality score (8.5 vs 9.5 EURONHEED scores; 24 vs 37 ISPOR scores). Most of the studies lacked a comprehensive view of all possible alternative strategies and clinical subgroups. Currency adjustment methods were rarely reported, as well as full range and distributions of input parameters. Moreover, introduction and discussion rarely faced implementation and generalizability as well as opportunity costs. Rarely a full comparison with previously published cost utility analyses was discussed. Expert commentary
Infliximab or adalimumab therapy followed by mid-term maintenance therapy for 1 or 2 years and subsequent shift to 820
another anti-TNF agent in case of failure can be cost-effective compared with nonbiological therapy in a long-term time horizon and a societal perspective, in the most appropriate clinical setting, that is, severe luminal disease or pediatric patients. Inconsistent results from different studies can be explained by different time horizons or different estimations of data missing from the literature, such as hospitalization rates. Moreover, heterogenous data sources for efficacy can also explain the results: head-to-head studies comparing different biological therapies are lacking as well as crossover studies. Timeframe of the analysis is critical because patients showed to be highly risk-averse [48]. Finally, real-life management of CD includes dose adjustments with dose escalations, as well as, on the opposite, noncompliance to the treatment plan. Productivity loss due to CD is relevant since the disease is usually diagnosed in the second or third decade of life: indirect costs account for 28% in the USA to nearly 69% in Europe of overall disease-related costs [49]. Amelioration of disease activity correlates positively with patient productivity and decreases indirect costs by about US$10,000 per year [50]. Despite international guidelines for pharmacoeconomic evaluations recommending a societal perspective for the analyses, only one of the retrieved study considered indirect costs. Budget silos usually make societal evaluations less appealing to healthcare decision-makers. Five-year view
The future CD management involves an outcomes-based approach supporting the choice among different treatment strategies based on clinical data at presentation but also on biological remission. Therefore, symptoms-based decisions will be replaced by decisions based on endoscopic healing [51–53]; however, the exact degree of mucosal healing that will lead to improved long-term remission, decreased hospital and surgical rates remains unknown. A ‘treat to target’ strategy based on regular assessment of disease activity by objective measures and Expert Rev. Pharmacoecon. Outcomes Res. 14(6), (2014)
Review
Biologic therapies in CD
Score 2 Score 1 or 2 56% 89%
Title specific for economic evaluation and listing compared options 33%
83%
Abstract including perspective, setting,input data, uncertainty analysis
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22%
100%
Introduction starting the decision making context 28% Target population and subgroups: full description and account
100% 28%
89%
Description of setting and location of the decision 67% Study perspective and related cost issues
100% 61%
100%
Compared strategie: full description and account 33%
100%
Time horizon stated 33%
83%
Discount rate reported and discussed 22%
89%
Outcomes described and relevance discussed 61%
94%
Single study-based effectiveness data: full description of the study 17%
94%
Synthesis-based effectiveness data: full description of methods 56%
94%
Preference-based outcomes: details of sources 39%
94%
Single study-based resource use and costs: full description 44%
83%
Model-based resource use and costs: full description 39% 67%
Currency: stated methods for adjustment to the year of reported cost 28%
78%
Model description (graphic) and account 17%
94%
Analythic methods for input data management 22%
78%
Study parameters: full description (incl range and probability distribution) 11%
89%
Incremental outcomes 61%
First-order uncertainty characterization (incl discount and perspective) 28%
100% 94%
Second-order uncertainty characterization (incl model structure and assumptions) 33% Subgroup and scenario analyses
100% 44%
100%
Limitations and generalizability of the results discussed Funding and support declared Conflict of interest described
78% 83% 67% 83%
Figure 3. Proportion of studies satisfying ISPOR criteria.
subsequent adjustment of treatments is a new paradigm for CD management [54,55]. We wish that central regulatory agencies, that is, EMA and FDA, provide general shared recommendations on standards for modeling in drug authorization submissions and academic studies. We expect that homogeneous definition of health informahealthcare.com
states, input data, relevant intermediate end points, study perspective and time horizon would improve comparability and generalizability of health economic assessments. Health economic dossiers would be submitted to decision-makers in the different countries in a very shorter time and decisions would be much more transparent. 821
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Review
Marchetti & Liberato
Willingness to pay for one QALY varies across countries and usually vary according to disease severity. Therefore, commonly adopted cost–effectiveness thresholds might not be justified for severe disabling diseases incurring in working-age people, like CD. Moreover, single rare diseases impose a lower burden onto healthcare budget of industrialized countries. Therefore, commonly adopted standard ICUR threshold might not be fully justified either by equity or by health economics [56]. Indeed, infliximab maintenance therapy has been authorized for refractory nonfistulizing CD by most industrialized countries despite an ambiguous economic profile in the perspective of third-
party payers, without an explicit consideration of a societal perspective or acceptability thresholds specific for rare diseases. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Several effective biological therapies are available for Crohn’s disease (CD), but optimal scheduling and sequence has not been ascertained yet. • Monoclonal antibodies for CD provide quality-of-life amelioration at an acceptable cost for value if maintenance therapy is tailored, an appropriate time horizon is adopted and societal costs are considered. • Mucosal healing is a candidate intermediate end point for personalizing therapies for CD: future decision models should consider estimation of long-term outcomes based on such a parameter. • Standard model structure and main input parameters should be centrally defined in order to allow full comparability among modelbased cost–effectiveness studies.
therapy in inflammatory bowel disease. Dig Liver Dis 2011;43(1):1-20
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Expert Rev. Pharmacoecon. Outcomes Res. 14(6), (2014)
