Determining the Value of Two Biologic Drugs for Chronic Inflammatory Skin Diseases: Results of a Multi-Criteria Decision Analysis

Determining the Value of Two Biologic Drugs for Chronic Inflammatory Skin Diseases: Results of a... BioDrugs (2018) 32:281–291 https://doi.org/10.1007/s40259-018-0284-3 OR IGINAL RESEARCH ARTIC L E Determining the Value of Two Biologic Drugs for Chronic Inflammatory Skin Diseases: Results of a Multi-Criteria Decision Analysis 1 1 1 2 • • • • Ne´boa Zozaya Lucı´a Martı´nez-Galdeano Bleric Alcala´ Jose Carlos Armario-Hita 3 4 5 6 • • • • Concepcio´n Carmona Jose Manuel Carrascosa Pedro Herranz Marı´a Jesu´s Lamas 7 8,9 Marta Trapero-Bertran Alvaro Hidalgo-Vega Published online: 29 May 2018 The Author(s) 2018 Abstract weighting (between 1 and 5) of each criterion with the Background and Objective Multi-criteria decision analysis individual scoring of each intervention in each criterion. (MCDA) is a tool that systematically considers multiple Dupilumab was evaluated against placebo, while secuk- factors relevant to health decision-making. The aim of this inumab was evaluated against placebo, etanercept and study was to use an MCDA to assess the value of dupilu- ustekinumab. A retest was performed to assess the repro- mab for severe atopic dermatitis compared with secuk- ducibility of weights, scores and value estimates. inumab for moderate to severe plaque psoriasis in Spain. Results The overall MCDA value estimate for dupilumab Method Following the EVIDEM (Evidence and Value: versus placebo was 0.51 ± 0.14. This value was higher Impact on DEcision Making) methodology, the estimated than those obtained for secukinumab: 0.48 ± 0.15 versus value of both interventions was obtained by means of an placebo, 0.45 ± 0.15 versus etanercept and 0.39 ± 0.18 additive linear model that combined the individual versus ustekinumab. The highest-value contribution was reported by the patients’ group, followed by the clinical professionals and the decision makers. A fundamental Electronic supplementary material The online version of this element that explained the difference in the scoring article (https://doi.org/10.1007/s40259-018-0284-3) contains supple- mentary material, which is available to authorized users. between pathologies was the availability of therapeutic alternatives. The retest confirmed the consistency and & Ne ´boa Zozaya replicability of the analysis. neboa.zozaya@weber.org.es Conclusions Under this methodology, and assuming sim- Department of Health Economics, Weber Economı ´a y Salud, ilar economic costs per patient for both treatments, the c/Norias 123, Majadahonda, 28221 Madrid, Spain results indicated that the overall value estimated of dupi- Department of Dermatology, University Hospital of Puerto lumab for severe atopic dermatitis was similar to, or Real, Puerto Real, Ca ´diz, Spain slightly higher than, that of secukinumab for moderate to Department of Healthcare, Servicio Extremen ˜ o de Salud, severe plaque psoriasis. Me ´rida, Badajoz, Spain Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain Department of Dermatology, La Paz Universitary Hospital- Carlos III, Madrid, Spain Servicio de Farmacia, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, La Corun ˜ a, Spain Faculty of Economics and Social Sciences, Universitat Internacional de Catalunya, Barcelona, Spain Fundacion Weber, Majadahonda, Madrid, Spain Universidad de Castilla-La Mancha, Campus de Toledo, Toledo, Spain 282 N. Zozaya et al. MCDA have focused on chronic inflammatory diseases [21]. Key Points Atopic dermatitis (AD) and psoriasis are two of the main dermatological diseases [22]; they are systemic, inflam- Multi-criteria decision analysis (MCDA) can matory, chronic and immunomediated dermatoses that improve the healthcare decision-making process by substantially reduce the quality of life of patients [23–25]. considering an explicit set of criteria and their Biological drugs are effective in the management and relative importance under a fully transparent process. control of severe forms of both diseases. In the case of This study approximated the overall estimated value psoriasis, therapeutic perspectives and clinical experience of two innovative drugs for chronic inflammatory is much more extensive, thanks to the existence of various skin diseases (atopic dermatitis and psoriasis) from a approved drugs. In contrast, there is currently only one broad and systematic view, while incorporating local officially approved biologic drug for AD, which is avail- multi-disciplinary views to express a societal able in a few countries. perspective. Dupilumab (Dupixent , Sanofi-Aventis Group, La Boetie, Paris, France), approved in 2017, is indicated to This exercise allows us to better understand where treat moderate to severe AD in adults who are candidates the value of dupilumab and secukinimab lies for the for systemic therapy. Prior to its authorisation, the only different stakeholders, providing useful information that could help to make better decisions on the treatment with approved indication for severe AD was ciclosporin (cyclosporine), which is effective in the man- assessment, pricing and public reimbursement of agement of the disease in the short-term but has a high risk these interventions. of cumulative toxicity; thus, it is not advisable to admin- ister for prolonged periods, limiting its use for the treat- ment of any chronic pathology [26]. Secukinumab (Cosentyx , Novartis Europharm Lim- ited, Camberley, United Kingdom), authorised in 2015, is a 1 Introduction biological drug indicated to treat moderate to severe plaque psoriasis in adults who are candidates for systemic treat- In healthcare, deciding the most appropriate and efficient ments. Its relevant comparators are other biological treat- allocation of resources is a difficult but necessary task that ments, such as etanercept, infliximab, adalimumab and requires consideration of multiple factors. The process ustekinumab. often utilises decision-supporting tools, such as economic The main objective of this study was to assess the value evaluation. However, cost-effectiveness analysis has some of dupilumab in the treatment of severe AD compared with limitations: it has been criticized for its rigidity and for not the value of secukinumab in the treatment of moderate to adequately capturing the social value of a drug [1–4]. severe plaque psoriasis in Spain, using the MCDA Given the need for a more systematic and explicit methodology. The advantage of comparing these drugs approach that takes into account factors relevant to society indirectly is better interpretation of the result for dupilu- simultaneously, multi-criteria decision analysis (MCDA) mab, contextualising it with that of secukinumab, a drug represents an emerging tool in health decision-making that that was authorised some years ago and is perceived as a aims to complement the cost-effectiveness analysis [5, 6]. high value-added medicine. MCDA allows participants to reflect and express clearly which criteria they are considering and how they are val- ued, introducing greater transparency, consistency and 2 Method accountability [7]. Also, MCDA helps people to face eth- ical dilemmas, and it provides a context for the promotion This study was designed following the Evidence and of multi-disciplinary dialogue based on evidence [6, 8–10]. Value: Impact on DEcision Making (EVIDEM) framework MCDA is a useful methodology that guides the making (version 3.1) for MCDA, a methodology widely used and of complex decisions, such as the funding or reimburse- based on the application and evaluation of a standard set of ment of healthcare interventions. Increasingly, it has been 13 quantitative criteria, obtaining an estimated overall used in real practice to prioritise different healthcare value of the intervention [27]. The EVIDEM framework interventions [7–17] or to assess the value of drugs also includes a contextual tool for qualitative criteria. [18–20]. Chronic disabling diseases, such as the most The steps taken to carry out the MCDA (Fig. 1) were serious dermatological pathologies, constitute an area in based on previously published good methodological prac- which MCDA can be especially useful. However, very few tices [7, 28]. A committee of ten experts was formed, MCDA to Evaluate Biological Drugs for Chronic Skin Diseases 283 Fig. 1 Study design comprising three clinicians (dermatologists), four patients generated, and individual experience and perception, each (two with severe psoriasis and two with severe AD), two expert assigned a score to each quantitative criterion for the regional payers and one health economist. Members were two interventions evaluated. The scores for the absolute selected based on their expertise, while trying to achieve a criteria (those that did not involve comparisons with balanced geographical representation. The consultancy alternative interventions) could range from 0 to 5, 0 being firm WEBER (Madrid, Spain) reached out to the panellists, the lowest value and 5 the highest. For relative criteria except for the patients, who were selected by their der- (those involving comparison with an alternative interven- matologists—also experts on this committee. WEBER was tion), the scale ranged from - 5 to 5 to reflect the full range responsible for training the experts committee on MCDA, of comparative effects (Electronic Supplementary Material reviewing and sharing the evidence with the panellists prior 2). The comparators were those contained in the pivotal to the meeting, coordinating the committee, and analysing clinical trials of the respective interventions. Thus, dupi- and presenting the results. lumab was evaluated only against placebo, whereas Following the EVIDEM methodology, the first step secukinumab was evaluated threefold: against placebo, consisted of assigning weights and was carried out online etanercept and ustekinumab. The impact of the seven before the experts knew the interventions to be evaluated. EVIDEM qualitative criteria was also discussed at the Each expert assigned a weight between 1 and 5 to each meeting, based on the available evidence (Electronic quantitative criterion according to its importance, 1 being Supplementary Material 3) and the stakeholders’ the least relevant and 5 the most. perception. The second step was carried out through a face-to-face The estimated value for each intervention was obtained meeting of the committee. Based on the available scientific through a linear additive model, combining the relative evidence (previously validated by the committee’s clini- weighting of each criterion with the reported score for each cians) (Electronic Supplementary Material 1), the debate intervention in each criterion. Each estimated value was 284 N. Zozaya et al. transformed into a 0–1 scale to facilitate its interpretation. makers (between 2.33 and 4.67) and patients (between 2.75 In particular, the following formula was used [8]: and 4.75) were lower and more similar to each other. The n n greatest discrepancies occurred between clinicians and X X V ¼ V ¼ S ; decision makers in the type of preventive benefit and the x x x¼1 x¼1 quality of evidence, and between clinicians and patients in the three variables of relative cost. where V is the total estimated value, V the value contri- bution of criterion x, W the weighting of criterion x, RW x n 3.2 Scores for Dupilumab the sum of all weights, and S the scoring of criterion x. To check the degree of consistency and replicability of Regarding the mean scores for dupilumab for severe AD the analysis, a retest was carried out several weeks after the (Fig. 3), the committee gave the highest score (4.8 out of 5) meeting. The experts re-evaluated the criteria, online, for and with the strongest consensus (SD 0.42) to the unmet both interventions, assigning weights and scores. The needs of the disease, highlighting the problems faced by degree of agreement between the responses made at the patients with severe AD, as they currently lack long-term two timepoints was evaluated through the intra-rater cor- effective and safe systemic therapies [23–25]. The severity relation coefficients (ICC 3,1) using STATA version 14 of the disease obtained the second highest score (STATA Corp., LP, College Station, TX, USA). (4.50 ± 0.85). The committee assessed the severe AD in the context of all the diseases that a patient may suffer, specifying that the pruritus is usually intense and influences 3 Results the mood, rest, relationships and daily activities of the patients, substantially reducing their quality of life [29–31]. 3.1 Panellists’ Weights Evidence indicating that moderate to severe AD has a greater impact on quality of life than other diseases, such as The panellists considered that all criteria had a high rela- psoriasis, especially in the field of mental health, was tive importance, giving all of them an average weight presented [32–35]. above 3 (out of 5) (Fig. 2). According to the committee, the According to the committee, dupilumab presents an most relevant criteria should be quality of evidence improvement in clinical efficacy (4.40 ± 0.84) and patient- (4.80 ± 0.42), comparative effectiveness/efficacy of the reported outcomes (PROs) (4.10 ± 1.20) versus placebo, intervention (4.60 ± 0.52) and disease severity as well as a higher therapeutic benefit (4.10 ± 0.74). In (4.40 ± 1.07). The least relevant criteria were the type of contrast, the score associated with the preventive benefit of preventive benefit (3.10 ± 1.29) and the size of the the treatment was 0.80 (SD 1.69). The greatest variability affected population (3.30 ± 0.67). The greatest variability occurred in the relative safety profile (SD 2.87). According in the responses was given to the type of benefit of the to the prevalence considered, the size of the population intervention, both preventive (standard deviation [SD] potentially affected by the intervention is estimated to be 1.29) and therapeutic (SD 1.20). between 4.9 and 9.8 of every 10,000 people in Spain. In general, the clinicians assigned the highest average Experts scored this criterion with an average score of weights (between 3.67 and 5.00), while those of decision Fig. 2 Mean weights for decision criteria by the advisory committee. A 5-point weighting scale was used, with 1 for the lowest weight and 5 for the highest weight MCDA to Evaluate Biological Drugs for Chronic Skin Diseases 285 Fig. 3 Mean scores for decision criteria for the appraisal of between 0 and 5), while the rest were evaluated in terms relative to dupilumab (vs. placebo) by the advisory committee. Criteria 1–3, placebo (with a score between – 5 and 5) 7–8 and 12–13 were evaluated in absolute terms (with a score 2.50 ± 0.53. The number of people indicated for treatment differences between the three groups (3.33 for decision with dupilumab, that is, non-responder patients with severe makers vs. 4.67 for clinicians and 5 for patients), as did the AD or who have contraindications or intolerance to sys- type of therapeutic benefit (3.33 vs. 4.33 and 4.5, temic immunosuppressive therapies, was taken into respectively). account. In terms of costs, given that there were still no real data 3.3 Scores for Secukinumab available for Spain, the committee relied on its own per- ception and personal experience. Because dupilumab is a It is important to note that the scoring of the absolute cri- first-in-class biological, the annual treatment cost per teria was common for the three comparisons (vs. placebo, patient was assumed to be the same as for secukinumab. etanercept and ustekinumab). The absolute criteria that This criterion was the only one where dupilumab obtained obtained higher scores were severity of the disease a negative average score (- 2.8 ± 1.55), which implies (4.30 ± 0.82) and type of therapeutic benefit that it was more expensive than its comparator (placebo). (4.30 ± 0.67), followed by quality of the evidence The other two cost criteria were scored positively, sug- (4.00 ± 0.94) (Fig. 4). Given the symptoms, co-morbidi- gesting that the treatment could produce savings on other ties and impairment of patients’ quality of life [40–42], the healthcare costs (1.10 ± 1.29), especially non-healthcare committee rated moderate to severe plaque psoriasis as costs (2.70 ± 1.64), thanks to the presumable reduction of highly severe but lower than severe AD (4.3 vs. 4.5). The losses of working or teaching hours due to better control of scientific evidence on secukinumab was assessed as rele- the disease [36, 37]. vant and well reported (4.00 ± 0.94), despite some limi- The quality of the evidence received a mean score of tations regarding the choice of comparators, their doses, the 3.70 (SD 1.34), meaning that the pivotal trials from which selected subpopulations and the effectiveness measurement the evidence came were deemed adequate [38, 39]. In bias [43–45]. contrast, the degree of alignment of dupilumab with current The intervention would affect a greater population size clinical practice guidelines (CPG) was considered low than dupilumab (27 per 10,000 people [46–48]), with this (1.40 ± 2.07), given that, due to its recent approval, it has criterion scored as 3.50 ± 0.85. Regarding the unmet not yet been included in the guidelines. needs at the time of the release of secukinumab, these were The analysis highlighted certain differences in the quantified as lower than for dupilumab, thanks to the opinions of the expert committee members. While patients existence of other highly effective biological drugs (2.1 vs. tended to assign the highest scores, decision makers were 4.8 for dupilumab). In view of the fact that the CPG place the least benevolent in the scoring of most of the criteria secukinumab as another treatment option, recommending it and the clinicians were the strictest in scoring safety and at the same level as the rest of the options [48–50], the cost of acquisition. For example, clinicians and patients committee assessed this criterion as having a score of unanimously scored the severity of the disease with the 1.00 ± 0.82. It was clear that the treatment did not offer a highest score, while it was not a chief concern for decision marked preventive benefit (0.10 ± 0.32). makers (3.33 ± 0.58). Efficacy scores showed large 286 N. Zozaya et al. Fig. 4 Mean scores for decision criteria for the appraisal of were applied equally to the three comparisons made, while criteria secukinumab (vs. placebo, etanercept and ustekinumab) by the 4–6 and 9–11 (orange markers) were evaluated in relative terms to the advisory committee. Criteria 1–3, 7–8 and 12–13 (blue markers) different comparators (with a score between - 5 and 5). ETN were evaluated in absolute terms (with a score between 0 and 5) and etanercept, PBO placebo, UTK ustekinumab The relative criteria were scored against the three 3.4 Value Estimates for Dupilumab and Secukinumab available comparators, resulting in a clear gradient. The most favourable scores were given versus placebo and the The overall estimated value integrated the weights and least favourable versus ustekinumab. When compared with placebo, efficacy and PROs were assessed with very high scores of each panellist on a scale between 0 and 1. Regarding the contribution of each criteria to the overall scores and a high degree of consensus (5.00 ± 0.00 and 4.90 ± 0.32, respectively). These scores decreased when value estimate for dupilumab and secukinumab (Fig. 5), compared with etanercept (3.70 ± 0.82 and 3.20 ± 1.40, both interventions were considered to provide a high added respectively) and ustekinumab (1.90 ± 1.45 and value versus their comparators. Specifically, the estimated 1.70 ± 1.83, respectively), as the difference in efficacy and value for dupilumab in severe AD, versus placebo, was PROs between treatments decreased [39, 43–45]. Con- 0.51 (95% confidence interval [CI] 0.42–0.61)]. This value cerning tolerability, secukinumab had an acceptable safety was higher than that obtained for secukinumab in moderate to severe plaque psoriasis, independent of the comparators profile, with similar adverse events than other biologic drugs indicated for psoriasis [44, 45]. considered: 0.48 (95% CI 0.37–0.59) versus placebo, 0.45 (95% CI 0.34–0.56) versus etanercept and 0.39 (95% CI Regarding the economic consequences, the committee distinguished the direct costs of the intervention (with a 0.27–0.52) versus ustekinumab. The greatest differences negative score vs. the comparators) from the rest of the between the value of dupilumab and secukinumab were resulting direct and indirect costs (with a positive relative due to the compared efficacy (0.08 vs. 0.03 when using score). The cost of the intervention was estimated based on ustekinumab as a comparator), followed by the cost of the the defined daily dose (according to the technical specifi- intervention (- 0.05 vs. - 0.01), unmet needs (0.07 vs. cations), the official drug price and the mandatory discount 0.03) and PROs (0.06 vs. 0.03). Approximately half of the estimated value of dupilumab applied in Spain [51, 52]. The annual cost per patient treated with secukinumab was assumed to be slightly lower was due to the positive contribution of four criteria: com- parative effectiveness/efficacy (13.0%), disease severity than that of ustekinumab and 36% higher than that of etanercept (which already had a biosimilar approved). The (12.8%), unmet needs (11.7%) and quality of evidence (11.5%). The comparative cost of the intervention was the average scores were - 3.00 ± 2.40 versus placebo, - 0.90 ± 1.60 versus etanercept and – 0.30 ± 2.20 versus only criterion that contributed negatively, reducing the ustekinumab. The committee considered that the treatment estimated value of dupilumab by 7.8% (Fig. 5a). with secukinumab would avoid some healthcare costs with For secukinumab, 65.8% of the estimated value versus respect to alternatives and reduce labour productivity los- placebo was due to the positive contribution of five criteria: ses [45, 53, 54]. comparative effectiveness/efficacy (15.5%), quality of The patients were also the group who gave the highest evidence (13.0%), comparative PROs (12.9%), severity of the disease (12.8%) and type of therapeutic benefit (11.6%) mean scores to the evaluated intervention. The greatest differences between expert groups were found for the rel- (Fig. 5b). The compared cost also contributed negatively to the overall estimated value (- 8.7%). When secukinumab ative criteria and for unmet needs (SD 1.91). was compared with alternative biologics, the relative MCDA to Evaluate Biological Drugs for Chronic Skin Diseases 287 Fig. 5 Mean value contributions of each quantitative criterion and makers and patients). Value contribution ¼ normalised weight overall value estimates for dupilumab and secukinumab. Average of normalised weight ¼ value contribution of all 13 criteria: ETN the committee of experts and for each group (clinicians, decision etanercept, PBO placebo, UTK ustekinumab criteria contributed less to the final value. In both cases, the 3.5 Replicability and Consistency criteria that contributed most to the estimated value were the quality of evidence (15.7% in the etanercept scenario The retest showed good reproducibility, with a relatively high degree of agreement and consistency of the results. and 18.6% in the ustekinumab scenario), severity of the disease (15.4 and 18.3%) and type of therapeutic benefit Between test and retest, 48% of weights were identical, 38% differed by 1 point and 14% differed by 2 or 3 points. (14.0 and 16.6%). In contrast, the negative contribution of the compared costs of the intervention had a smaller impact The greatest inconsistency was recorded for the patients’ on the value estimate for secukinumab (3.3% vs. etanercept subgroup. The ICC for weights was 0.52. Scores showed a and 1.4% vs. ustekinumab) (Fig. 5c, d). slightly better consistency than weights: 59% were identi- cal in the case of dupilumab and 53, 57 and 60% in the case 288 N. Zozaya et al. of secukinumab (vs. placebo, etanercept and ustekinumab, in the placebo scenario, from 14 to 23% in the scenario respectively). The greatest divergences occurred in type of with etanercept and from 30 to 38% in the scenario with preventive benefit, severity of the disease and compared ustekinumab. cost of the intervention. The intra-rater correlation between scores was slightly higher for dupilumab (0.802) than for 3.6 Qualitative Criteria secukinumab (0.763 vs. placebo, 0.750 vs. etanercept and 0.735 vs. ustekinumab). The panellists also assessed the impact of each qualitative The value estimate obtained in the retest for the two criterion on both interventions (Electronic Supplementary interventions was consistent with that of the primary Material 4). Given the lack of accurate and relevant evi- analysis. The value for dupilumab was 0.55 (95% CI dence, together with some difficulties of interpretation, the 0.44–0.66) (6.4% higher than the original value), thanks to contextual tool represents complementary information that the greater relative contribution of unmet needs, PROs, supports a wider overview of the MCDA framework. type of therapeutic benefit, other healthcare costs and quality of evidence (Table 1). The improvement in the overall value estimate was significant in the group of 4 Discussion decision makers (? 27%), compared with a lesser improvement among patients (? 5.3%) and a decrease The aim of our study was to assess the value of dupilumab among clinicians (- 8.8%). for severe AD compared with the value of secukinumab for The retest performed for secukinumab also showed moderate to severe plaque psoriasis in Spain, using an consistent figures with the original analysis. The estimated MCDA. To our knowledge, this is the first MCDA applied value remained lower than that obtained for dupilumab, in the field of dermatology in Spain and the first MCDA again showing a clear gradient between comparators: 0.50 that estimates the value of a treatment for AD. Our work (95% CI 0.36–0.63) versus placebo, 0.44 (95% CI has made it possible to numerically approximate an overall 0.31–0.58) versus etanercept and 0.40 (95% CI 0.25–0.54) value estimate for two innovative medicines from a broader vs. ustekinumab (Table 1). The degree of correlation perspective than usual, taking into account fundamental between the overall values at both timepoints for secuk- additional elements. Although there is still no evidence on inumab was higher than for dupilumab. indirect comparisons between both drugs, the juxtaposition Despite the relatively high degree of agreement and of AD and psoriasis is not new [55, 56]. The availability of consistency between test and retest, the differences therapeutic alternatives was a relevant differential element. between the values of both drugs increased from 7 to 11% Currently, severe AD is a chronic disease with many unmet Table 1 Estimated value for dupilumab and secukinumab in the test and the retest Intervention Comparator Expert committee subgroup Test Retest Difference (%) ICC (3,1) individual ICC (3,1) average Dupilumab Placebo Total (n = 10) 0.514 0.547 6.4 0.614 0.761 Clinicians (n = 3) 0.459 0.419 - 8.8 - 0.101 - 0.226 Decision makers/HE (n = 3) 0.382 0.486 27.2 0.015 0.030 Patients (n = 4) 0.655 0.690 5.3 - 0.420 - 1.450 Secukinumab Placebo Total (n = 10) 0.480 0.495 3.0 0.915 0.956 Clinicians (n = 3) 0.374 0.364 - 2.7 0.613 0.760 Decision makers/HE (n = 3) 0.368 0.362 - 1.6 - 0.065 - 0.140 Patients (n = 4) 0.645 0.694 7.5 0.953 0.976 ETN Total (n = 10) 0.450 0.443 - 1.5 0.963 0.981 Clinicians (n = 3) 0.369 0.352 - 4.6 0.964 0.982 Decision makers/HE (n = 3) 0.314 0.290 - 7.8 0.982 0.991 Patients (n = 4) 0.613 0.628 2.4 0.837 0.911 UTK Total (n = 10) 0.394 0.395 0.2 0.928 0.963 Clinicians (n = 3) 0.310 0.287 - 7.4 0.273 0.429 Decision-makers/HE (n = 3) 0.240 0.251 4.7 - 0.032 - 0.066 Patients (n = 4) 0.573 0.584 1.9 0.815 0.898 ETN etanercept, HE health economist, ICC intra-rater correlation coefficients, UTK ustekinumab MCDA to Evaluate Biological Drugs for Chronic Skin Diseases 289 needs. By contrast, the psoriasis context is radically dif- allows for the use of validated criteria and is in continuous ferent because there are different biological drugs that can review and evolution. Secondly, it is a subjective exercise, manage the disease effectively and safely. In addition, the results of which depend, to a large extent, on the severe AD was deemed to have a greater impact on quality composition of the evaluation committee, and the value of life than psoriasis. judgements, experience and training of its members. Our study was able to compare, to a certain extent, the However, the fact that the same committee evaluated both results obtained for both drugs, given that both AD and drugs facilitates the comparison of the results. Thirdly, psoriasis are chronic inflammatory diseases, the two drugs MCDA can be complex for some agents, which can lead to evaluated are biologics that were commercialized recently misinterpretation of some of the evidence and/or scoring and the assessment was performed by the same committee. scales. We tried to alleviate this limitation by sending each The results suggest that the two evaluated biologicals member complete information on the methodology and constitute interventions of high added value. The innova- evidence, in an understandable language, prior to the tive drug selected for severe AD (dupilumab) obtained an meeting. Lastly, the representativeness of the results at a overall value estimate of 0.51 points. This figure was national level is limited by the small number of experts that similar to that of the drug selected for moderate to severe made up the committee. Nevertheless, the number of plaque psoriasis (secukinumab) when compared with pla- experts included is in line with other MCDA studies carried cebo (0.48 points) and slightly higher than secukinumab out for a specific intervention, between eight and 19 when compared with its two alternatives (0.45 and 0.39). experts [8, 57, 58]. As expected, the estimated value for secukinumab We should also note the influence of both the com- decreased as the performance of its comparator increased. parator used and the time of execution on the final result, as The retest revealed fair to good consistency of the results. the valuation obtained is not generalizable to other com- Despite the multi-disciplinary debate, differences among parators, nor does it last over time. Finally, the value stakeholders persisted. estimates of the MCDA are not intended to be used in a To contextualize, the estimated values are slightly above prescriptive manner, but rather as a further element of the range of values obtained in the literature for other discussion that serves as a basis for ordering interventions innovative drugs to which the MCDA–EVIDEM frame- and complementing pharmacoeconomic analyses, which work was applied. For example, obinutuzumab for ritux- usually lack this broader perspective [8, 60]. imab-refractory indolent non-Hodgkin lymphoma obtained a value of 0.45 in Italy, tramadol for chronic non-cancer pain had a value of 0.44 in Canada, growth hormone for 5 Conclusions Turner syndrome had a value of 0.41 in Canada, and len- vatinib for radio-iodine-refractory differentiated thyroid This study applied an MCDA to the evaluation of two cancer had a value between 0.33 and 0.38 in Spain innovative biological drugs aimed at treating chronic [8, 57–59]. inflammatory diseases in Spain. The results show the high The panellists noted that the exercise was useful and added value posed by both drugs from a multi-disciplinary interesting, and that the exchange of opinions between perspective, under a methodological umbrella that takes them enriched the analysis and individual assessments. into account a wide spectrum of value attributes. Assuming However, they also stressed that it required some famil- a similar annual economic cost per patient for both treat- iarity with the assessment of medications, the amount of ments, the results confirm that dupilumab as a therapy for evidence provided, and the type of concepts and language severe AD has a final estimated value similar to or slightly used. In this regard, it is important to emphasise the higher than secukinumab for moderate to severe plaque importance of providing the best possible understanding, psoriasis. This exercise allows us to understand better especially to patients, the group least familiar with this type where the value of health interventions lies for the different of exercise. On the other hand, the differences between the agents. It is presented as a tool aimed to help agents to types of experts that made up the committee is worth make decisions on the assessment, pricing and public noting. Both their weightings and scores inevitably con- reimbursement of health interventions. In the future, it formed to their own perceptions, experience, training and would be desirable to continue developing MCDA and to value judgements, and therefore shows the importance of extend its use, so that decision-making takes place in a having this multi-disciplinary vision. framework of greater transparency, consistency and effi- The study is not exempt from certain limitations. First, it ciency, serving as a complementary tool to economic carries the inherent limitations of the EVIDEM approach, evaluation. which includes a fixed set of criteria and, therefore, may exclude other relevant criteria. However, this methodology 290 N. Zozaya et al. Acknowledgements We want to thank Carlos Asenjo Barahona, 10. Gilabert-Perramon A, Torrent-Farnell J, Catalan A, Prat A, ´ ´ Agustı Infiesta Aguila, Jaime Llaneza Manrique de Lara and Diego Fontanet M, Puig-Peiro R, et al. Drug evaluation and decision Navarro Martı ´nez for their valuable contributions to this project, by making in Catalonia: development and validation of a method- participating as patients in the advisory committee and contributing ological framework based on multi-criteria decision analysis their suggestions to improve the final manuscript. (MCDA) for orphan drugs. Int J Technol Assess Health Care. 2017;33(1):111–20. 11. Youngkong S, Baltussen R, Tantivess S, Mohara A, Teerawat- Compliance with Ethical Standards tananon Y. Multicriteria decision analysis for including health interventions in the universal health coverage benefit package in Funding The project was financed by Sanofi Spain. Their partici- Thailand. Value Health. 2012;15:961–70. pation was limited to sponsoring the project; they were not present at 12. Drake JI, de Hart JCT, Monleo ´ n C, Toro W, Valentim J. the face-to-face meeting of the advisory committee and had no input Utilization of multiple-criteria decision analysis (MCDA) to into the writing of the manuscript. support healthcare decision-making FIFARMA, 2016. J Mark Access Health Policy. 2017;5(1):1360545. Conflict of interest The authors (NZ, LMG, BA, JCAH, CC, JMC, 13. Defechereux T, Paolucci F, Mirelman A, Youngkong S, Botten PH, MJL, MTB and AHV) declare no conflicts of interest that are G, Hagen TP, et al. Health care priority setting in Norway a relevant to the content of this study. CC did not receive any support multicriteria decision analysis. BMC Health Serv Res. from the sponsor of this submitted work. 2012;12:39. 14. Wilson EC, Rees J, Fordham RJ. Developing a prioritisation Open Access This article is distributed under the terms of the framework in an English Primary Care Trust. 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Determining the Value of Two Biologic Drugs for Chronic Inflammatory Skin Diseases: Results of a Multi-Criteria Decision Analysis

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Abstract

BioDrugs (2018) 32:281–291 https://doi.org/10.1007/s40259-018-0284-3 OR IGINAL RESEARCH ARTIC L E Determining the Value of Two Biologic Drugs for Chronic Inflammatory Skin Diseases: Results of a Multi-Criteria Decision Analysis 1 1 1 2 • • • • Ne´boa Zozaya Lucı´a Martı´nez-Galdeano Bleric Alcala´ Jose Carlos Armario-Hita 3 4 5 6 • • • • Concepcio´n Carmona Jose Manuel Carrascosa Pedro Herranz Marı´a Jesu´s Lamas 7 8,9 Marta Trapero-Bertran Alvaro Hidalgo-Vega Published online: 29 May 2018 The Author(s) 2018 Abstract weighting (between 1 and 5) of each criterion with the Background and Objective Multi-criteria decision analysis individual scoring of each intervention in each criterion. (MCDA) is a tool that systematically considers multiple Dupilumab was evaluated against placebo, while secuk- factors relevant to health decision-making. The aim of this inumab was evaluated against placebo, etanercept and study was to use an MCDA to assess the value of dupilu- ustekinumab. A retest was performed to assess the repro- mab for severe atopic dermatitis compared with secuk- ducibility of weights, scores and value estimates. inumab for moderate to severe plaque psoriasis in Spain. Results The overall MCDA value estimate for dupilumab Method Following the EVIDEM (Evidence and Value: versus placebo was 0.51 ± 0.14. This value was higher Impact on DEcision Making) methodology, the estimated than those obtained for secukinumab: 0.48 ± 0.15 versus value of both interventions was obtained by means of an placebo, 0.45 ± 0.15 versus etanercept and 0.39 ± 0.18 additive linear model that combined the individual versus ustekinumab. The highest-value contribution was reported by the patients’ group, followed by the clinical professionals and the decision makers. A fundamental Electronic supplementary material The online version of this element that explained the difference in the scoring article (https://doi.org/10.1007/s40259-018-0284-3) contains supple- mentary material, which is available to authorized users. between pathologies was the availability of therapeutic alternatives. The retest confirmed the consistency and & Ne ´boa Zozaya replicability of the analysis. neboa.zozaya@weber.org.es Conclusions Under this methodology, and assuming sim- Department of Health Economics, Weber Economı ´a y Salud, ilar economic costs per patient for both treatments, the c/Norias 123, Majadahonda, 28221 Madrid, Spain results indicated that the overall value estimated of dupi- Department of Dermatology, University Hospital of Puerto lumab for severe atopic dermatitis was similar to, or Real, Puerto Real, Ca ´diz, Spain slightly higher than, that of secukinumab for moderate to Department of Healthcare, Servicio Extremen ˜ o de Salud, severe plaque psoriasis. Me ´rida, Badajoz, Spain Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain Department of Dermatology, La Paz Universitary Hospital- Carlos III, Madrid, Spain Servicio de Farmacia, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, La Corun ˜ a, Spain Faculty of Economics and Social Sciences, Universitat Internacional de Catalunya, Barcelona, Spain Fundacion Weber, Majadahonda, Madrid, Spain Universidad de Castilla-La Mancha, Campus de Toledo, Toledo, Spain 282 N. Zozaya et al. MCDA have focused on chronic inflammatory diseases [21]. Key Points Atopic dermatitis (AD) and psoriasis are two of the main dermatological diseases [22]; they are systemic, inflam- Multi-criteria decision analysis (MCDA) can matory, chronic and immunomediated dermatoses that improve the healthcare decision-making process by substantially reduce the quality of life of patients [23–25]. considering an explicit set of criteria and their Biological drugs are effective in the management and relative importance under a fully transparent process. control of severe forms of both diseases. In the case of This study approximated the overall estimated value psoriasis, therapeutic perspectives and clinical experience of two innovative drugs for chronic inflammatory is much more extensive, thanks to the existence of various skin diseases (atopic dermatitis and psoriasis) from a approved drugs. In contrast, there is currently only one broad and systematic view, while incorporating local officially approved biologic drug for AD, which is avail- multi-disciplinary views to express a societal able in a few countries. perspective. Dupilumab (Dupixent , Sanofi-Aventis Group, La Boetie, Paris, France), approved in 2017, is indicated to This exercise allows us to better understand where treat moderate to severe AD in adults who are candidates the value of dupilumab and secukinimab lies for the for systemic therapy. Prior to its authorisation, the only different stakeholders, providing useful information that could help to make better decisions on the treatment with approved indication for severe AD was ciclosporin (cyclosporine), which is effective in the man- assessment, pricing and public reimbursement of agement of the disease in the short-term but has a high risk these interventions. of cumulative toxicity; thus, it is not advisable to admin- ister for prolonged periods, limiting its use for the treat- ment of any chronic pathology [26]. Secukinumab (Cosentyx , Novartis Europharm Lim- ited, Camberley, United Kingdom), authorised in 2015, is a 1 Introduction biological drug indicated to treat moderate to severe plaque psoriasis in adults who are candidates for systemic treat- In healthcare, deciding the most appropriate and efficient ments. Its relevant comparators are other biological treat- allocation of resources is a difficult but necessary task that ments, such as etanercept, infliximab, adalimumab and requires consideration of multiple factors. The process ustekinumab. often utilises decision-supporting tools, such as economic The main objective of this study was to assess the value evaluation. However, cost-effectiveness analysis has some of dupilumab in the treatment of severe AD compared with limitations: it has been criticized for its rigidity and for not the value of secukinumab in the treatment of moderate to adequately capturing the social value of a drug [1–4]. severe plaque psoriasis in Spain, using the MCDA Given the need for a more systematic and explicit methodology. The advantage of comparing these drugs approach that takes into account factors relevant to society indirectly is better interpretation of the result for dupilu- simultaneously, multi-criteria decision analysis (MCDA) mab, contextualising it with that of secukinumab, a drug represents an emerging tool in health decision-making that that was authorised some years ago and is perceived as a aims to complement the cost-effectiveness analysis [5, 6]. high value-added medicine. MCDA allows participants to reflect and express clearly which criteria they are considering and how they are val- ued, introducing greater transparency, consistency and 2 Method accountability [7]. Also, MCDA helps people to face eth- ical dilemmas, and it provides a context for the promotion This study was designed following the Evidence and of multi-disciplinary dialogue based on evidence [6, 8–10]. Value: Impact on DEcision Making (EVIDEM) framework MCDA is a useful methodology that guides the making (version 3.1) for MCDA, a methodology widely used and of complex decisions, such as the funding or reimburse- based on the application and evaluation of a standard set of ment of healthcare interventions. Increasingly, it has been 13 quantitative criteria, obtaining an estimated overall used in real practice to prioritise different healthcare value of the intervention [27]. The EVIDEM framework interventions [7–17] or to assess the value of drugs also includes a contextual tool for qualitative criteria. [18–20]. Chronic disabling diseases, such as the most The steps taken to carry out the MCDA (Fig. 1) were serious dermatological pathologies, constitute an area in based on previously published good methodological prac- which MCDA can be especially useful. However, very few tices [7, 28]. A committee of ten experts was formed, MCDA to Evaluate Biological Drugs for Chronic Skin Diseases 283 Fig. 1 Study design comprising three clinicians (dermatologists), four patients generated, and individual experience and perception, each (two with severe psoriasis and two with severe AD), two expert assigned a score to each quantitative criterion for the regional payers and one health economist. Members were two interventions evaluated. The scores for the absolute selected based on their expertise, while trying to achieve a criteria (those that did not involve comparisons with balanced geographical representation. The consultancy alternative interventions) could range from 0 to 5, 0 being firm WEBER (Madrid, Spain) reached out to the panellists, the lowest value and 5 the highest. For relative criteria except for the patients, who were selected by their der- (those involving comparison with an alternative interven- matologists—also experts on this committee. WEBER was tion), the scale ranged from - 5 to 5 to reflect the full range responsible for training the experts committee on MCDA, of comparative effects (Electronic Supplementary Material reviewing and sharing the evidence with the panellists prior 2). The comparators were those contained in the pivotal to the meeting, coordinating the committee, and analysing clinical trials of the respective interventions. Thus, dupi- and presenting the results. lumab was evaluated only against placebo, whereas Following the EVIDEM methodology, the first step secukinumab was evaluated threefold: against placebo, consisted of assigning weights and was carried out online etanercept and ustekinumab. The impact of the seven before the experts knew the interventions to be evaluated. EVIDEM qualitative criteria was also discussed at the Each expert assigned a weight between 1 and 5 to each meeting, based on the available evidence (Electronic quantitative criterion according to its importance, 1 being Supplementary Material 3) and the stakeholders’ the least relevant and 5 the most. perception. The second step was carried out through a face-to-face The estimated value for each intervention was obtained meeting of the committee. Based on the available scientific through a linear additive model, combining the relative evidence (previously validated by the committee’s clini- weighting of each criterion with the reported score for each cians) (Electronic Supplementary Material 1), the debate intervention in each criterion. Each estimated value was 284 N. Zozaya et al. transformed into a 0–1 scale to facilitate its interpretation. makers (between 2.33 and 4.67) and patients (between 2.75 In particular, the following formula was used [8]: and 4.75) were lower and more similar to each other. The n n greatest discrepancies occurred between clinicians and X X V ¼ V ¼ S ; decision makers in the type of preventive benefit and the x x x¼1 x¼1 quality of evidence, and between clinicians and patients in the three variables of relative cost. where V is the total estimated value, V the value contri- bution of criterion x, W the weighting of criterion x, RW x n 3.2 Scores for Dupilumab the sum of all weights, and S the scoring of criterion x. To check the degree of consistency and replicability of Regarding the mean scores for dupilumab for severe AD the analysis, a retest was carried out several weeks after the (Fig. 3), the committee gave the highest score (4.8 out of 5) meeting. The experts re-evaluated the criteria, online, for and with the strongest consensus (SD 0.42) to the unmet both interventions, assigning weights and scores. The needs of the disease, highlighting the problems faced by degree of agreement between the responses made at the patients with severe AD, as they currently lack long-term two timepoints was evaluated through the intra-rater cor- effective and safe systemic therapies [23–25]. The severity relation coefficients (ICC 3,1) using STATA version 14 of the disease obtained the second highest score (STATA Corp., LP, College Station, TX, USA). (4.50 ± 0.85). The committee assessed the severe AD in the context of all the diseases that a patient may suffer, specifying that the pruritus is usually intense and influences 3 Results the mood, rest, relationships and daily activities of the patients, substantially reducing their quality of life [29–31]. 3.1 Panellists’ Weights Evidence indicating that moderate to severe AD has a greater impact on quality of life than other diseases, such as The panellists considered that all criteria had a high rela- psoriasis, especially in the field of mental health, was tive importance, giving all of them an average weight presented [32–35]. above 3 (out of 5) (Fig. 2). According to the committee, the According to the committee, dupilumab presents an most relevant criteria should be quality of evidence improvement in clinical efficacy (4.40 ± 0.84) and patient- (4.80 ± 0.42), comparative effectiveness/efficacy of the reported outcomes (PROs) (4.10 ± 1.20) versus placebo, intervention (4.60 ± 0.52) and disease severity as well as a higher therapeutic benefit (4.10 ± 0.74). In (4.40 ± 1.07). The least relevant criteria were the type of contrast, the score associated with the preventive benefit of preventive benefit (3.10 ± 1.29) and the size of the the treatment was 0.80 (SD 1.69). The greatest variability affected population (3.30 ± 0.67). The greatest variability occurred in the relative safety profile (SD 2.87). According in the responses was given to the type of benefit of the to the prevalence considered, the size of the population intervention, both preventive (standard deviation [SD] potentially affected by the intervention is estimated to be 1.29) and therapeutic (SD 1.20). between 4.9 and 9.8 of every 10,000 people in Spain. In general, the clinicians assigned the highest average Experts scored this criterion with an average score of weights (between 3.67 and 5.00), while those of decision Fig. 2 Mean weights for decision criteria by the advisory committee. A 5-point weighting scale was used, with 1 for the lowest weight and 5 for the highest weight MCDA to Evaluate Biological Drugs for Chronic Skin Diseases 285 Fig. 3 Mean scores for decision criteria for the appraisal of between 0 and 5), while the rest were evaluated in terms relative to dupilumab (vs. placebo) by the advisory committee. Criteria 1–3, placebo (with a score between – 5 and 5) 7–8 and 12–13 were evaluated in absolute terms (with a score 2.50 ± 0.53. The number of people indicated for treatment differences between the three groups (3.33 for decision with dupilumab, that is, non-responder patients with severe makers vs. 4.67 for clinicians and 5 for patients), as did the AD or who have contraindications or intolerance to sys- type of therapeutic benefit (3.33 vs. 4.33 and 4.5, temic immunosuppressive therapies, was taken into respectively). account. In terms of costs, given that there were still no real data 3.3 Scores for Secukinumab available for Spain, the committee relied on its own per- ception and personal experience. Because dupilumab is a It is important to note that the scoring of the absolute cri- first-in-class biological, the annual treatment cost per teria was common for the three comparisons (vs. placebo, patient was assumed to be the same as for secukinumab. etanercept and ustekinumab). The absolute criteria that This criterion was the only one where dupilumab obtained obtained higher scores were severity of the disease a negative average score (- 2.8 ± 1.55), which implies (4.30 ± 0.82) and type of therapeutic benefit that it was more expensive than its comparator (placebo). (4.30 ± 0.67), followed by quality of the evidence The other two cost criteria were scored positively, sug- (4.00 ± 0.94) (Fig. 4). Given the symptoms, co-morbidi- gesting that the treatment could produce savings on other ties and impairment of patients’ quality of life [40–42], the healthcare costs (1.10 ± 1.29), especially non-healthcare committee rated moderate to severe plaque psoriasis as costs (2.70 ± 1.64), thanks to the presumable reduction of highly severe but lower than severe AD (4.3 vs. 4.5). The losses of working or teaching hours due to better control of scientific evidence on secukinumab was assessed as rele- the disease [36, 37]. vant and well reported (4.00 ± 0.94), despite some limi- The quality of the evidence received a mean score of tations regarding the choice of comparators, their doses, the 3.70 (SD 1.34), meaning that the pivotal trials from which selected subpopulations and the effectiveness measurement the evidence came were deemed adequate [38, 39]. In bias [43–45]. contrast, the degree of alignment of dupilumab with current The intervention would affect a greater population size clinical practice guidelines (CPG) was considered low than dupilumab (27 per 10,000 people [46–48]), with this (1.40 ± 2.07), given that, due to its recent approval, it has criterion scored as 3.50 ± 0.85. Regarding the unmet not yet been included in the guidelines. needs at the time of the release of secukinumab, these were The analysis highlighted certain differences in the quantified as lower than for dupilumab, thanks to the opinions of the expert committee members. While patients existence of other highly effective biological drugs (2.1 vs. tended to assign the highest scores, decision makers were 4.8 for dupilumab). In view of the fact that the CPG place the least benevolent in the scoring of most of the criteria secukinumab as another treatment option, recommending it and the clinicians were the strictest in scoring safety and at the same level as the rest of the options [48–50], the cost of acquisition. For example, clinicians and patients committee assessed this criterion as having a score of unanimously scored the severity of the disease with the 1.00 ± 0.82. It was clear that the treatment did not offer a highest score, while it was not a chief concern for decision marked preventive benefit (0.10 ± 0.32). makers (3.33 ± 0.58). Efficacy scores showed large 286 N. Zozaya et al. Fig. 4 Mean scores for decision criteria for the appraisal of were applied equally to the three comparisons made, while criteria secukinumab (vs. placebo, etanercept and ustekinumab) by the 4–6 and 9–11 (orange markers) were evaluated in relative terms to the advisory committee. Criteria 1–3, 7–8 and 12–13 (blue markers) different comparators (with a score between - 5 and 5). ETN were evaluated in absolute terms (with a score between 0 and 5) and etanercept, PBO placebo, UTK ustekinumab The relative criteria were scored against the three 3.4 Value Estimates for Dupilumab and Secukinumab available comparators, resulting in a clear gradient. The most favourable scores were given versus placebo and the The overall estimated value integrated the weights and least favourable versus ustekinumab. When compared with placebo, efficacy and PROs were assessed with very high scores of each panellist on a scale between 0 and 1. Regarding the contribution of each criteria to the overall scores and a high degree of consensus (5.00 ± 0.00 and 4.90 ± 0.32, respectively). These scores decreased when value estimate for dupilumab and secukinumab (Fig. 5), compared with etanercept (3.70 ± 0.82 and 3.20 ± 1.40, both interventions were considered to provide a high added respectively) and ustekinumab (1.90 ± 1.45 and value versus their comparators. Specifically, the estimated 1.70 ± 1.83, respectively), as the difference in efficacy and value for dupilumab in severe AD, versus placebo, was PROs between treatments decreased [39, 43–45]. Con- 0.51 (95% confidence interval [CI] 0.42–0.61)]. This value cerning tolerability, secukinumab had an acceptable safety was higher than that obtained for secukinumab in moderate to severe plaque psoriasis, independent of the comparators profile, with similar adverse events than other biologic drugs indicated for psoriasis [44, 45]. considered: 0.48 (95% CI 0.37–0.59) versus placebo, 0.45 (95% CI 0.34–0.56) versus etanercept and 0.39 (95% CI Regarding the economic consequences, the committee distinguished the direct costs of the intervention (with a 0.27–0.52) versus ustekinumab. The greatest differences negative score vs. the comparators) from the rest of the between the value of dupilumab and secukinumab were resulting direct and indirect costs (with a positive relative due to the compared efficacy (0.08 vs. 0.03 when using score). The cost of the intervention was estimated based on ustekinumab as a comparator), followed by the cost of the the defined daily dose (according to the technical specifi- intervention (- 0.05 vs. - 0.01), unmet needs (0.07 vs. cations), the official drug price and the mandatory discount 0.03) and PROs (0.06 vs. 0.03). Approximately half of the estimated value of dupilumab applied in Spain [51, 52]. The annual cost per patient treated with secukinumab was assumed to be slightly lower was due to the positive contribution of four criteria: com- parative effectiveness/efficacy (13.0%), disease severity than that of ustekinumab and 36% higher than that of etanercept (which already had a biosimilar approved). The (12.8%), unmet needs (11.7%) and quality of evidence (11.5%). The comparative cost of the intervention was the average scores were - 3.00 ± 2.40 versus placebo, - 0.90 ± 1.60 versus etanercept and – 0.30 ± 2.20 versus only criterion that contributed negatively, reducing the ustekinumab. The committee considered that the treatment estimated value of dupilumab by 7.8% (Fig. 5a). with secukinumab would avoid some healthcare costs with For secukinumab, 65.8% of the estimated value versus respect to alternatives and reduce labour productivity los- placebo was due to the positive contribution of five criteria: ses [45, 53, 54]. comparative effectiveness/efficacy (15.5%), quality of The patients were also the group who gave the highest evidence (13.0%), comparative PROs (12.9%), severity of the disease (12.8%) and type of therapeutic benefit (11.6%) mean scores to the evaluated intervention. The greatest differences between expert groups were found for the rel- (Fig. 5b). The compared cost also contributed negatively to the overall estimated value (- 8.7%). When secukinumab ative criteria and for unmet needs (SD 1.91). was compared with alternative biologics, the relative MCDA to Evaluate Biological Drugs for Chronic Skin Diseases 287 Fig. 5 Mean value contributions of each quantitative criterion and makers and patients). Value contribution ¼ normalised weight overall value estimates for dupilumab and secukinumab. Average of normalised weight ¼ value contribution of all 13 criteria: ETN the committee of experts and for each group (clinicians, decision etanercept, PBO placebo, UTK ustekinumab criteria contributed less to the final value. In both cases, the 3.5 Replicability and Consistency criteria that contributed most to the estimated value were the quality of evidence (15.7% in the etanercept scenario The retest showed good reproducibility, with a relatively high degree of agreement and consistency of the results. and 18.6% in the ustekinumab scenario), severity of the disease (15.4 and 18.3%) and type of therapeutic benefit Between test and retest, 48% of weights were identical, 38% differed by 1 point and 14% differed by 2 or 3 points. (14.0 and 16.6%). In contrast, the negative contribution of the compared costs of the intervention had a smaller impact The greatest inconsistency was recorded for the patients’ on the value estimate for secukinumab (3.3% vs. etanercept subgroup. The ICC for weights was 0.52. Scores showed a and 1.4% vs. ustekinumab) (Fig. 5c, d). slightly better consistency than weights: 59% were identi- cal in the case of dupilumab and 53, 57 and 60% in the case 288 N. Zozaya et al. of secukinumab (vs. placebo, etanercept and ustekinumab, in the placebo scenario, from 14 to 23% in the scenario respectively). The greatest divergences occurred in type of with etanercept and from 30 to 38% in the scenario with preventive benefit, severity of the disease and compared ustekinumab. cost of the intervention. The intra-rater correlation between scores was slightly higher for dupilumab (0.802) than for 3.6 Qualitative Criteria secukinumab (0.763 vs. placebo, 0.750 vs. etanercept and 0.735 vs. ustekinumab). The panellists also assessed the impact of each qualitative The value estimate obtained in the retest for the two criterion on both interventions (Electronic Supplementary interventions was consistent with that of the primary Material 4). Given the lack of accurate and relevant evi- analysis. The value for dupilumab was 0.55 (95% CI dence, together with some difficulties of interpretation, the 0.44–0.66) (6.4% higher than the original value), thanks to contextual tool represents complementary information that the greater relative contribution of unmet needs, PROs, supports a wider overview of the MCDA framework. type of therapeutic benefit, other healthcare costs and quality of evidence (Table 1). The improvement in the overall value estimate was significant in the group of 4 Discussion decision makers (? 27%), compared with a lesser improvement among patients (? 5.3%) and a decrease The aim of our study was to assess the value of dupilumab among clinicians (- 8.8%). for severe AD compared with the value of secukinumab for The retest performed for secukinumab also showed moderate to severe plaque psoriasis in Spain, using an consistent figures with the original analysis. The estimated MCDA. To our knowledge, this is the first MCDA applied value remained lower than that obtained for dupilumab, in the field of dermatology in Spain and the first MCDA again showing a clear gradient between comparators: 0.50 that estimates the value of a treatment for AD. Our work (95% CI 0.36–0.63) versus placebo, 0.44 (95% CI has made it possible to numerically approximate an overall 0.31–0.58) versus etanercept and 0.40 (95% CI 0.25–0.54) value estimate for two innovative medicines from a broader vs. ustekinumab (Table 1). The degree of correlation perspective than usual, taking into account fundamental between the overall values at both timepoints for secuk- additional elements. Although there is still no evidence on inumab was higher than for dupilumab. indirect comparisons between both drugs, the juxtaposition Despite the relatively high degree of agreement and of AD and psoriasis is not new [55, 56]. The availability of consistency between test and retest, the differences therapeutic alternatives was a relevant differential element. between the values of both drugs increased from 7 to 11% Currently, severe AD is a chronic disease with many unmet Table 1 Estimated value for dupilumab and secukinumab in the test and the retest Intervention Comparator Expert committee subgroup Test Retest Difference (%) ICC (3,1) individual ICC (3,1) average Dupilumab Placebo Total (n = 10) 0.514 0.547 6.4 0.614 0.761 Clinicians (n = 3) 0.459 0.419 - 8.8 - 0.101 - 0.226 Decision makers/HE (n = 3) 0.382 0.486 27.2 0.015 0.030 Patients (n = 4) 0.655 0.690 5.3 - 0.420 - 1.450 Secukinumab Placebo Total (n = 10) 0.480 0.495 3.0 0.915 0.956 Clinicians (n = 3) 0.374 0.364 - 2.7 0.613 0.760 Decision makers/HE (n = 3) 0.368 0.362 - 1.6 - 0.065 - 0.140 Patients (n = 4) 0.645 0.694 7.5 0.953 0.976 ETN Total (n = 10) 0.450 0.443 - 1.5 0.963 0.981 Clinicians (n = 3) 0.369 0.352 - 4.6 0.964 0.982 Decision makers/HE (n = 3) 0.314 0.290 - 7.8 0.982 0.991 Patients (n = 4) 0.613 0.628 2.4 0.837 0.911 UTK Total (n = 10) 0.394 0.395 0.2 0.928 0.963 Clinicians (n = 3) 0.310 0.287 - 7.4 0.273 0.429 Decision-makers/HE (n = 3) 0.240 0.251 4.7 - 0.032 - 0.066 Patients (n = 4) 0.573 0.584 1.9 0.815 0.898 ETN etanercept, HE health economist, ICC intra-rater correlation coefficients, UTK ustekinumab MCDA to Evaluate Biological Drugs for Chronic Skin Diseases 289 needs. By contrast, the psoriasis context is radically dif- allows for the use of validated criteria and is in continuous ferent because there are different biological drugs that can review and evolution. Secondly, it is a subjective exercise, manage the disease effectively and safely. In addition, the results of which depend, to a large extent, on the severe AD was deemed to have a greater impact on quality composition of the evaluation committee, and the value of life than psoriasis. judgements, experience and training of its members. Our study was able to compare, to a certain extent, the However, the fact that the same committee evaluated both results obtained for both drugs, given that both AD and drugs facilitates the comparison of the results. Thirdly, psoriasis are chronic inflammatory diseases, the two drugs MCDA can be complex for some agents, which can lead to evaluated are biologics that were commercialized recently misinterpretation of some of the evidence and/or scoring and the assessment was performed by the same committee. scales. We tried to alleviate this limitation by sending each The results suggest that the two evaluated biologicals member complete information on the methodology and constitute interventions of high added value. The innova- evidence, in an understandable language, prior to the tive drug selected for severe AD (dupilumab) obtained an meeting. Lastly, the representativeness of the results at a overall value estimate of 0.51 points. This figure was national level is limited by the small number of experts that similar to that of the drug selected for moderate to severe made up the committee. Nevertheless, the number of plaque psoriasis (secukinumab) when compared with pla- experts included is in line with other MCDA studies carried cebo (0.48 points) and slightly higher than secukinumab out for a specific intervention, between eight and 19 when compared with its two alternatives (0.45 and 0.39). experts [8, 57, 58]. As expected, the estimated value for secukinumab We should also note the influence of both the com- decreased as the performance of its comparator increased. parator used and the time of execution on the final result, as The retest revealed fair to good consistency of the results. the valuation obtained is not generalizable to other com- Despite the multi-disciplinary debate, differences among parators, nor does it last over time. Finally, the value stakeholders persisted. estimates of the MCDA are not intended to be used in a To contextualize, the estimated values are slightly above prescriptive manner, but rather as a further element of the range of values obtained in the literature for other discussion that serves as a basis for ordering interventions innovative drugs to which the MCDA–EVIDEM frame- and complementing pharmacoeconomic analyses, which work was applied. For example, obinutuzumab for ritux- usually lack this broader perspective [8, 60]. imab-refractory indolent non-Hodgkin lymphoma obtained a value of 0.45 in Italy, tramadol for chronic non-cancer pain had a value of 0.44 in Canada, growth hormone for 5 Conclusions Turner syndrome had a value of 0.41 in Canada, and len- vatinib for radio-iodine-refractory differentiated thyroid This study applied an MCDA to the evaluation of two cancer had a value between 0.33 and 0.38 in Spain innovative biological drugs aimed at treating chronic [8, 57–59]. inflammatory diseases in Spain. The results show the high The panellists noted that the exercise was useful and added value posed by both drugs from a multi-disciplinary interesting, and that the exchange of opinions between perspective, under a methodological umbrella that takes them enriched the analysis and individual assessments. into account a wide spectrum of value attributes. Assuming However, they also stressed that it required some famil- a similar annual economic cost per patient for both treat- iarity with the assessment of medications, the amount of ments, the results confirm that dupilumab as a therapy for evidence provided, and the type of concepts and language severe AD has a final estimated value similar to or slightly used. In this regard, it is important to emphasise the higher than secukinumab for moderate to severe plaque importance of providing the best possible understanding, psoriasis. This exercise allows us to understand better especially to patients, the group least familiar with this type where the value of health interventions lies for the different of exercise. On the other hand, the differences between the agents. It is presented as a tool aimed to help agents to types of experts that made up the committee is worth make decisions on the assessment, pricing and public noting. Both their weightings and scores inevitably con- reimbursement of health interventions. In the future, it formed to their own perceptions, experience, training and would be desirable to continue developing MCDA and to value judgements, and therefore shows the importance of extend its use, so that decision-making takes place in a having this multi-disciplinary vision. framework of greater transparency, consistency and effi- The study is not exempt from certain limitations. First, it ciency, serving as a complementary tool to economic carries the inherent limitations of the EVIDEM approach, evaluation. which includes a fixed set of criteria and, therefore, may exclude other relevant criteria. However, this methodology 290 N. Zozaya et al. Acknowledgements We want to thank Carlos Asenjo Barahona, 10. Gilabert-Perramon A, Torrent-Farnell J, Catalan A, Prat A, ´ ´ Agustı Infiesta Aguila, Jaime Llaneza Manrique de Lara and Diego Fontanet M, Puig-Peiro R, et al. Drug evaluation and decision Navarro Martı ´nez for their valuable contributions to this project, by making in Catalonia: development and validation of a method- participating as patients in the advisory committee and contributing ological framework based on multi-criteria decision analysis their suggestions to improve the final manuscript. (MCDA) for orphan drugs. Int J Technol Assess Health Care. 2017;33(1):111–20. 11. Youngkong S, Baltussen R, Tantivess S, Mohara A, Teerawat- Compliance with Ethical Standards tananon Y. Multicriteria decision analysis for including health interventions in the universal health coverage benefit package in Funding The project was financed by Sanofi Spain. Their partici- Thailand. Value Health. 2012;15:961–70. pation was limited to sponsoring the project; they were not present at 12. Drake JI, de Hart JCT, Monleo ´ n C, Toro W, Valentim J. the face-to-face meeting of the advisory committee and had no input Utilization of multiple-criteria decision analysis (MCDA) to into the writing of the manuscript. support healthcare decision-making FIFARMA, 2016. J Mark Access Health Policy. 2017;5(1):1360545. Conflict of interest The authors (NZ, LMG, BA, JCAH, CC, JMC, 13. Defechereux T, Paolucci F, Mirelman A, Youngkong S, Botten PH, MJL, MTB and AHV) declare no conflicts of interest that are G, Hagen TP, et al. Health care priority setting in Norway a relevant to the content of this study. CC did not receive any support multicriteria decision analysis. BMC Health Serv Res. from the sponsor of this submitted work. 2012;12:39. 14. Wilson EC, Rees J, Fordham RJ. Developing a prioritisation Open Access This article is distributed under the terms of the framework in an English Primary Care Trust. 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Journal

BioDrugsSpringer Journals

Published: May 29, 2018

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