Integrating Health Technology Assessment and Multi-Criteria Decision Analysis in Optimizing Diabetic Macular Edema Management: Results from an Italian Multi-Regional Study

Background:


Introduction
Health Technology Assessment (HTA) is a widely implemented technical tool used to inform the decision-making process by providing policymakers with objective and relevant data, thus improving the efficiency in the allocation of resources [1]. The main feature of HTA is the possibility of including different perspectives, with an evidence-based approach, in the comparison of different technologies [2], thus investigating their economic, social, clinical, ethical, and organisational implications [3]. HTA Agencies and practitioners worldwide have acknowledged HTA as being "the gold standard" (i.e. reference practice), for identifying and selecting the most promising innovations in healthcare, avoiding waste on innovations that do not generate "enough value", in relation to their costs [4]. It should be noted that the definition of healthcare technologies ranges from biopharmaceuticals and diagnostics to medical devices, thus also including clinical procedures and clinical pathways [5], requiring the implementation of HTA practices for all the different categories of healthcare technology, and ensuring a quantitative evaluation, both in the assessment, and in the appraisal phase. Although HTA can be adopted for the assessment of any healthcare technology, the formal requirement of a multidimensional and multi-disciplinary approach as a necessary prerequisite for the systematic adoption of the technology varies across healthcare systems. Italian law [6] for example requires the implementation of an HTA approach for medical devices.
Given the significance of correctly assessing the impact of the adoption of a healthcare technology, it is important to carry out a complete HTA evaluation that does not focus solely on cost and effectiveness parameters due to scarce economic resources or time constraints. On the one hand, the literature [7] has reported how the use of a mini-HTA [8] could generate, in many cases, insufficient Model [4], often takes a significant amount of time, absorbing a substantial quantity of human and economic resources [9].
Whilst HTA's are often based, explicitly or otherwise, on the EUnetHTA Core Model, the appraisal can be further supported [9] through the use of a Multi-Criteria Decision Analysis (MCDA) approach [10][11]. The combination of both approaches allows for the achievement of a final quantitative comparison of the technologies evaluated, taking into account multiple criteria, in an explicit manner [12]. This provides a quantitative report for payers and decision makers developed in a transparent manner, aimed at supporting the decision-making process [10][11]. Despite the use of MCDA in healthcare, as an alternative methodological approach for assessing the value of healthcare interventions, ranging from licensing decisions at the marketing authorization stage [13][14], to coverage decisions at the HTA stage [10,15], or to treatment selection decisions at prescribing level [16][17], there is little documented about the integration of HTA and MCDA [1].
Focusing on the comparison between healthcare technologies available for the treatment of a specific pathology, the setting of the diabetic macular edema (DME) represents an excellent opportunity for a case study of the integration between HTA and MCDA. One of the most significant healthcare expenditure items, in the ophthalmological setting, is that devoted to intravitreal drugs used for the treatment of maculopathies. DME is a disabling and prevalent maculopathy, affecting on average 6.81% of the diabetic population, thus generating significant social and economic burden.
Given the scale of this disease and, above all, its growing potential impact in the future, due to the increasing incidence of diabetes and to the ageing population, it is becoming ever-more necessary to improve patient access to DME treatment strategies and, at the same time, to understand the opportunity for optimizing the cost of such strategies.
The present study aimed at evaluating the implementation of an HTA multi-dimensional approach, integrated with a multicriteria decision analysis in the appraisal phase, in the context of the therapeutic technologies licensed for DME treatment (Ranibizumab, Dexamethasone and Aflibercept). The study was developed within four Italian regions: Lombardy, Liguria, Tuscany and Veneto, thus testing the robustness of the combined approach, in four different regional settings.

Methods
In order to achieve the above-mentioned objective, a multidimensional comparison of principal treatments available was carried out, using the EUnetHTA Core Model [4] and MCDA [10][11]. In particular, the investigated treatments were Ranibizumab Dexamethasone received higher scores in the safety and efficacy dimensions (p=0.002). The appraisals in all 4 regions demonstrated that Dexamethasone implant received a higher overall score than the comparator technologies.

Conclusions:
The evaluation demonstrates that multi-criteria decision analysis can enhance the technology assessment process, providing decision makers with a robust method of assessing the preferable treatment options, for patients suffering from diabetic macular edema.
(reimbursed for the treatment of DME since December 2012), Aflibercept (reimbursed since March 2015), and Dexamethasone implant (initially reimbursed for second-line "off-label" use in DME from July 2014, then fully reimbursed from August 2015), all utilized within the Lombardy, Liguria, Tuscany and Veneto regions.
It should be noted here, that the drug bevacizumab, despite its use in some countries [18][19][20], was not included in the present evaluation in DME patients, since its use is only foreseen by the Italian NHS for patients with "wet age-related" macular degeneration.
The following study design, consisting of three distinct phases, was implemented.

A.
Production dimension, via a 3-level rating score (from "1" low performing to "3" high performing). Further details with regard the methods used for the enhancement of each dimension, as well as the criteria evaluated for MCDA are listed in Table 1.
Once having collected all the information, inferential analyses were conducted. In particular, the investigation statistically significant differences, was performed by means of "one-way" Anova tests between the attributed scores of the evaluators, comparing the four appraisals with each other, in order to identify how closely they matched. All statistical analyses were  Definition of the populated with diagnosis of DME, in accordance with the Italian epidemiological data available, both at national and at regional levels.
1 -Small number of potentially DME affected patients 2-Moderate number of potentially DME affected patients 3-Significant number of potentially DME affected patients

Description and Technical Characteristics
Definition of the benefits related to all the licensed drugs available in the clinical practice, for DME treatment. Identification of the possible drug-related adverse events for DME patients, in terms of evidencebased incidence-rate data derived from literature evidence available on the topic. These events were also economically evaluated, in order to analyze their economic impact, considering the NHS perspective, in accordance with the standard clinical pathways, declared by hospitals involved in the study -according to the Delphi methods, consistent with International and National HIV Guidelines, and Regional Clinical Pathways.

Clinical effectiveness Efficacy indicators
Identification of the clinical benefits related to the use of the licenced drugs for DME treatment, in terms of capability of the therapeutic strategy to ….
1 -The prevention strategy presents a significant increase in HIV occurrence rate 2 -The prevention strategy presents no impact in HIV occurrence rate 3 -The prevention strategy presents a significant decrease in HIV occurrence rate

Costs and economic evaluation Activity Based Costing Analysis
Clinical pathway economic evaluation, considering patients treated with ranibizumab, aflibercept, and dexamethasone, assuming the regional healthcare services point of view, and considering a 12-month time horizon.
1 -The intravitreal drug presents a substantial economic impact on the clinical pathway 2-The intravitreal drug presents an insignificant and sustainable economic impact on the clinical pathway 3 -The intravitreal drug presents a favorable and low economic impact on the clinical pathway

Budget impact analysis
The above-mentioned clinical pathway cost per DME patients, was multiplied by the total number of patients potentially eligible to DME treatment thus comparing a baseline scenario (consisting of Ranibizumab intravitreal injections alone), was compared with various different innovative scenarios consisting of the introduction of both aflibercept and dexamethasone therapeutic strategies.
1 -The intravitreal drug presents a substantial economic impact on the regional healthcare service 2 -The intravitreal drug presents an insignificant and sustainable impact on the regional healthcare service 1 -The intravitreal drug presents a favorable economic impact on the regional healthcare service

Equity aspects
Perceived aspects related to the access to care The equity aspect was examined by means of a qualitative questionnaire, completed by 21 healthcare professionals, based on a 7-item Likert scale (ranging from -3 to +3), considering the following items: 1) Impact on the access to care; 2) Impact on the hospital waiting lists; 3) Access to care, including people on a legally protected status; 4) Impact on caregivers' quality of life; 5) Impact on the patients' retention in care.
1 -The intravitreal drug presents a decrease in the access to care for DME patients at local level 2 -The intravitreal drug presents no impact in the access to care for DME patients at local level 3 -The intravitreal drug presents an increase in the access to care for DME patients at local level

Social aspects
Social and Ethical perceived aspects: the clinicians' point of view The social and ethical aspect was examined by means of a qualitative questionnaire, completed by 21 healthcare professionals, based on a 7-item Likert scale (ranging from -3 to +3), considering the following items.
1) Ability of the drug to protect the patients' autonomy. 2) Ability of the drug to protect the human rights. 3) Ability of the drug to protect the patients' integrity. 4) Ability of the drug to protect the patients' dignity. 5) Impact of the drug on the patients' willingness to pay. 6) Impact of the drug on the patients' religion. 7) Impact of the drug on social costs. 8) Impact of the drug on the patients' perceived quality of life.
1) Ability of the drug to protect the patients' autonomy. 2) Ability of the drug to protect the human rights. 3) Ability of the drug to protect the patients' integrity. 4) Ability of the drug to protect the patients' dignity. 5) Impact of the drug on the patients' willingness to pay. 6) Impact of the drug on the patients' religion. 7) Impact of the drug on social costs. 8) Impact of the drug on the patients' perceived quality of life.

-The intravitreal drug presents no impact in individuals reported outcomes, considering the clinicians' perspective
Legal aspects Legal perceived aspects The ethical aspect was examined by means of a qualitative questionnaire, completed by 21 healthcare professionals, based on a 7-item Likert scale (ranging from -3 to +3), considering the following items.
1) Authorization level (national/ European/ international). 2) Legal impact on safety issues. 3) Infringement of intellectual property rights. 4) Impact on the production warranties. 5) Need to regulate the drug acquisition and costs. 6) The legislation covers the regulation of technology, for all categories of users.
1 -The intravitreal drug presents the need to regulate its acquisition 2 -The intravitreal drug presents no need to regulate its acquisition 3 -The intravitreal drug presents an improvement of the related legal concerns Organizational aspects Organizational perceived aspects The ethical aspect was examined by means of a qualitative questionnaire, completed by 21 healthcare professionals, based on a 7-item Likert scale (ranging from -3 to +3), considering the following items.
. 1) Additional staff. 2) Training courses devoted to clinicians. 3) Training courses devoted to healthcare professionals. 4) Internal hospital meetings. 5) Additional rooms and services. 6) Additional furniture. 7) Impact on the internal processes. 8) Impact on the processes between the Pharmaceutical Department and the Ophthalmology Department. 9) Impact on the number of access. 1 -The intravitreal drug requires important and significant organizational investments in OR time for the conduction of the injection to the DME eligible population.

-
The intravitreal drug requires no or small organizational investment in OR time for the conduction of the injection, to the DME eligible population.
3 -The intravitreal drug presents the possibility to free-up organizational resources, with a decrease of OR time for the conduction of the injection, to the DME eligible population. pharmacists. As mentioned previously, following the prioritization of the dimensions, 12 HTA experts (3 per region) reviewed each of the regional reports and assessed the quality of information related to each treatment option, giving a numerical value for each dimension using a 3-level rating score (from "0" low performing to "3" high performing), for each sub-domain.

Results from the HTA
The four HTA reports showed similar overall results across the four regional settings [21][22][23][24]. Ranibizumab, Aflibercept and Dexamethasone present similar clinical efficacy, whilst they differ with regards to the number of injections required, and adverse events (AEs) occurring [25][26][27]. Consequently, the reports all found that the preferable treatment option within the DME target population would be the Dexamethasone implant [22][23].
Furthermore, it was evident that DME could be considered an    Table 2 shows detailed information with reference to both the economic and the organizational advantages. The utilization of the Dexamethasone implant was found to lead to significant economic savings for the four Regional

Results from the MCDA
As a first step, the dimensions of the EUnetHTA Core model were prioritized [28], to assess the weight of each of these aspects within the pathology being analysed, thus ordering the variables examined from the most important and highly prioritized (a score of 1) to the least relevant and least prioritized (a score of 7), as shown in Table   3. No statistically significant "between-region" differences emerged regarding the prioritization of the dimensions, except for the equity domain (p-value=0.013), that showed significant inter-regional variability. Twelve HTA experts were enrolled as external evaluators to review the HTA reports and evaluate each technology within each dimension and sub-dimensions, in accordance with a 3-level evaluation scale Table 4. The results showed that the evaluators, albeit having different professional roles and working in different

Discussion
The present study demonstrates that the MCDA approach can be employed to enhance the HTA process, synthesizing the technologies' "real value", through a numerical quantification, thus facilitating the decision-making process as well as giving information with regard to stakeholder preferences in a transparent way. The integration of HTA and MCDA, would also provide decision makers with a robust rationale, for the assignment and implementation of a preferred treatment option. In the general context of limited economic resources, it is increasingly important to be able justify treatment choices in terms of value to the system as well as to the individual patient, thus being consistent with the literature defining the importance of using MCDA in hospitals as an acknowledged method to support transparent and evidencebased decision-making [29][30]. Despite the application of a multidimensional approach to technology assessment being mandatory in the Italian setting only for medical devices [6], the analysis of the data suggests that HTA and MCDA could be implemented together for the assessment of other types of healthcare technologies such as drug treatments. The present study, with the production of four HTA reports following the EUnetHTA Core Model approach, also provides decision makers with a complete picture of opportunities and threats regarding the technological choices in DME. As reported in the literature [9], the methodology used in this analysis, is replicable in every setting of interest for being complete and simple to undertake, underlying the relevance to produce a full HTA report, without focusing the attention only on specific domains.
Furthermore, despite inter-regional variability in the relative