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SUMMARY Objective The objective of this study is to evaluate the economic benefits of immunoglobulin replacement therapy achieved subcutaneously (subcutaneous immunoglobulin, SCIG) by the rapid push method compared to intravenous infusion therapy (intravenous immunoglobulin, IVIG) in primary immune deficiency ( PID) patients from the healthcare system perspective in the context of the adult SCIG home infusion program based at St Paul's Hospital, Vancouver, Canada. Materials and methods SCIG and IVIG options were compared in cost-minimisation and budget impact models (BIMs) over 3 years. Sensitivity analyses were performed for both models to evaluate the impact of varying modality of IVIG treatments and proportion of patients switching from IVIG to SCIG. Results The cost-minimisation model estimated that SCIG treatment reduced cost to the healthcare system per patient of $5736 over 3 years, principally because of less use of hospital personnel. This figure varied between $5035 and $8739 depending on modality of IVIG therapy. Assuming 50% of patients receiving IVIG switched to SCIG, the BIM estimated cost savings for the first 3 years at $1·308 million or 37% of the personnel and supply budget. These figures varied between $1·148 million and $2·454 million (36 and 42%) with varying modalities of IVIG therapy. If 75% of patients switched to SCIG, the reduced costs reached $1·962 million or 56% of total budget. Conclusion This study demonstrated that from the health system perspective, rapid push home-based SCIG was less costly than hospital-based IVIG for immunoglobulin replacement therapy in adult PID patients in the Canadian context. [ABSTRACT FROM AUTHOR]

Butter fat was interesterified in a cosurfactant-free microemulsion system containing nonionic and ionic surfactants, using commercial lipase obtained from Rhizopus niveus, at different concentrations of surfactant mixtures and hydrophilic-lipophilic balance (HLB) values. The results indicated that the interesterification yield (IY) of lipasecatalyzed interesterified butter fat reached its maximum in the microemulsion system prepared with the surfactant mixture of HLB value of 9, followed by that of HLB value of 10. In addition, increasing concentrations of surfactant mixtures, from 3 to 6 mM, resulted by an increase in the IY. The interesterification of butter fat in the microemulsion prepared with 3 mM of surfactant mixture of HLB value of 10 showed a minimum hydrolytic activity. The results showed that the interesterified selected triacylglycerol molecules were enriched with the hypocholesterolemic fatty acid C18:l, originally located on sn-1,3 positions, on their sn-2 positions; this fatty acid was favorably interchanged with the hypercholesterolemic fatty acid C16:0, originally located on sn-2 position. The results also indicated that the use of 6 mM of surfactant mixtures increased the acyl exchange reaction toward the long-chain saturated fatty acid C16:0 on the sn-2 position of triacylglycerol molecules. [ABSTRACT FROM AUTHOR]

The partially purified chlorophyllase, obtained from the alga Phaeodactylum tricornutum, was further purified by preparative native gel electrophoresis. The purification procedure provided the recovery of large amounts of a single purified chlorophyllase fraction. However, the electrophoretic analyses of the purified enzymatic fraction under denaturing conditions demonstrated the presence of two bands with mol wt of 43 ±3 and 46 ±3 kDa. The purification procedure resulted in 2-and 195-fold increases in chlorophyllase activity compared to that of the partially purified and crude enzymatic extracts, respectively. The optimum pH for chlorophyllase hydrolytic activity was found to be 8.0. The optimum incubation time and temperature for the hydrolytic activity of the purified chlorophyllase were found to be 2 h and 31°C, respectively. The optimum concentrations of magnesium chloride and dithiothreitol, used as activators, were 4 and 5 mM, respectively. The addition of individual plant membrane lipids, including phosphatidylcholine, phosphatidylglycerol, and β-carotene, to the reaction media increased the enzyme activity markedly. The purified enzyme fraction displayed preferential specificity toward selective substrates with an order of activity as follows: purified chlorophyll b > purified chlorophyll a > partially purified chlorophyll > crude chlorophyll. Diisopropyl fluorophosphate and phytol, respectively, showed noncompetitive and competitive inhibitory effects on chlorophyllase activity with K, values of 0.78 mM and 3.75 μM, respectively. [ABSTRACT FROM AUTHOR]

Introduces articles in volume 3, issue 6 of 'Value in Health' which consider the economics of deep vein thrombosis (DVT) prophylaxis. Cost effectiveness of DVT after hospital discharge; Average cost of extended DVT.

Objectives: We provide guidance for considering equity in rapid reviews through examples of published COVID-19 rapid reviews., Study Design and Setting: This guidance was developed based on a series of methodological meetings, review of internationally renowned guidance such as the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for equity-focused systematic reviews (PRISMA-Equity) guideline. We identified Exemplar rapid reviews by searching COVID-19 databases and requesting examples from our team., Results: We proposed the following key steps: 1. involve relevant stakeholders with lived experience in the conduct and design of the review; 2. reflect on equity, inclusion and privilege in team values and composition; 3. develop research question to assess health inequities; 4. conduct searches in relevant disciplinary databases; 5. collect data and critically appraise recruitment, retention and attrition for populations experiencing inequities; 6. analyse evidence on equity; 7. evaluate the applicability of findings to populations experiencing inequities; and 8. adhere to reporting guidelines for communicating review findings. We illustrated these methods through rapid review examples., Conclusion: Implementing this guidance could contribute to improving equity considerations in rapid reviews produced in public health emergencies, and help policymakers better understand the distributional impact of diseases on the population., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Context: The increasing pressure on primary care services calls for efficient approaches to assess the potential value of innovations and identify facilitators to their deployment in local contexts. Objective: To explore the value arguments of innovations in primary care identified as promising during Quebec College of Family Physicians' Symposia on Innovations and to propose avenues for their improvement and deployment. Methods: Ten innovations were selected using their ranking at the Symposia and pre-established criteria to ensure diversity. An evidence-informed multidimensional deliberative approach (clinical, populational, economic, organizational and sociocultural dimensions) was applied by a panel of 12 clinicians, managers, patients and citizens. Using data synthesized by dimension, each participant identified arguments on the value of each innovation and appraised them on a numerical scale. The arguments were discussed by the group, and a qualitative analysis with inter-rater validation of the deliberation was performed and the mean appraisal scores at the group level were calculated. These qualitative and quantitative data were synthesized and used as a basis for a second discussion with the group during which avenues for deployment were organized by thematic analysis. Results: Innovations fell into three categories: support for clinical processes (n=5), adaptation of the organization of care to vulnerable populations (n=3), and support for quality improvement (n=2). Innovations aiming at adapting the organization of care for vulnerable populations were considered of highest value overall. Quality improvement innovations received mixed appraisals and needed to be further developed in terms of their value proposition and organizational fit. Innovations to support clinical processes also received mixed appraisals; proposals for further development included keeping them up to date and integrating them with information systems. Conclusions: This study highlights the factors that influence the value of certain categories of primary care innovations as well as avenues for their improvement and implementation that can guide innovators. This work demonstrates that exploring complex innovations with a multidimensional deliberative approach including patients and citizens is useful to identify their value arguments from a comprehensive standpoint, which is essential to identify the best implementation avenues to optimize the creation of value in real life., Competing Interests: Authors report none., (© 2021 Annals of Family Medicine, Inc.)

The application of artificial intelligence (AI) may revolutionize the healthcare system, leading to enhance efficiency by automatizing routine tasks and decreasing health-related costs, broadening access to healthcare delivery, targeting more precisely patient needs, and assisting clinicians in their decision-making. For these benefits to materialize, governments and health authorities must regulate AI, and conduct appropriate health technology assessment (HTA). Many authors have highlighted that AI health technologies (AIHT) challenge traditional evaluation and regulatory processes. To inform and support HTA organizations and regulators in adapting their processes to AIHTs, we conducted a systematic review of the literature on the challenges posed by AIHTs in HTA and health regulation. Our research question was: What makes artificial intelligence exceptional in HTA? The current body of literature appears to portray AIHTs as being exceptional to HTA. This exceptionalism is expressed along 5 dimensions: 1) AIHT's distinctive features; 2) their systemic impacts on health care and the health sector; 3) the increased expectations towards AI in health; 4) the new ethical, social and legal challenges that arise from deploying AI in the health sector; and 5) the new evaluative constraints that AI poses to HTA. Thus, AIHTs are perceived as exceptional because of their technological characteristics and potential impacts on society at large. As AI implementation by governments and health organizations carries risks of generating new, and amplifying existing, challenges, there are strong arguments for taking into consideration the exceptional aspects of AIHTs, especially as their impacts on the healthcare system will be far greater than that of drugs and medical devices. As AIHTs begin to be increasingly introduced into the health care sector, there is a window of opportunity for HTA agencies and scholars to consider AIHTs' exceptionalism and to work towards only deploying clinically, economically, socially acceptable AIHTs in the health care system., Competing Interests: IGC serves as a bioethics consultant for Otsuka on their Abilify MyCite product, is a member of the Illumina ethics advisory Board, and serves as an ethics consultant for Dawnlight. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bélisle-Pipon, Couture, Roy, Ganache, Goetghebeur and Cohen.)

Legitimacy of deliberation processes leading to recommendations for public financing or clinical practice depends on the data considered, stakeholders involved and the process by which both of these are selected and organised. Oortwijn et al provides an interesting exploration of processes currently in place in health technology assessment (HTA) agencies. However, agencies are struggling with core issues central to their legitimacy that goes beyond the procedural exploration of Oortwijn et al, such as: how processes reflect the mission and values of the agencies? How they ensure that recommendations are fair and reasonable? Which role should be given to public and patient involvement? Do agencies have a positive impact on the healthcare system and the populations served? What are the drivers of their evolution? We concur with Culyer commentary on the need of learning from doing what works best and that a reflection is indeed needed to "enhance the fairness and legitimacy of HTA.", (© 2021 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/ licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Context: The National Institute of Excellence in Health and Social Services (INESSS), which functions as the Québec health technology assessment (HTA) agency, tested a new way to engage patients along with health-care professionals in the co-construction of recommendations regarding implantable cardioverter-defibrillator replacement., Objective: The objective of this article was to describe the process of co-construction of recommendations and to propose methods of building best practices for patient involvement (PI) in HTA., Design: Throughout the process, documents were collected and participant observations were made. Individual interviews were conducted with patients, health-care professionals and the INESSS scientific team, from January to March 2018., Results: Three committees were established: an expert patient committee to reflect on patient experience literature; an expert health professional committee to reflect on medical literature; and a co-construction committee through which both patients and health-care professionals contributed to develop the recommendations. The expert patients validated and contextualized a literature review produced by the scientific team. This allowed the scientists to consider aspects related to the patient experience and to integrate the feedback from patients into HTA recommendations. The most important factor contributing to a positive PI experience was the structured methodology for selecting patient participants, and a key factor that inhibited the process was a lack of training in PI on the part of the scientific team., Conclusions: This experience demonstrates that it is possible to co-construct recommendations, even for technically complex HTA subjects, through a more democratic process than usual which led to more patient-focused guidance., (© 2019 The Authors Health Expectations published by John Wiley & Sons Ltd.)

Introduction: Well- or moderately differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are often slow-growing, and some patients with unresectable, asymptomatic, non-functioning tumors may face the choice between watchful waiting (WW), or somatostatin analogues (SSA) to delay progression. We developed a comprehensive multi-criteria decision analysis (MCDA) framework to help patients and physicians clarify their values and preferences, consider each decision criterion, and support communication and shared decision-making., Methods: The framework was adapted from a generic MCDA framework (EVIDEM) with patient and clinician input. During a workshop, patients and clinicians expressed their individual values and preferences (criteria weights) and, on the basis of two scenarios (treatment vs WW; SSA-1 [lanreotide] vs SSA-2 [octreotide]) with evidence from a literature review, expressed how consideration of each criterion would impact their decision in favor of either option (score), and shared their knowledge and insights verbally and in writing., Results: The framework included benefit-risk criteria and modulating factors, such as disease severity, quality of evidence, costs, and constraints. Overall and progression-free survival being most important, criteria weights ranged widely, highlighting variations in individual values and the need to share them. Scoring and considering each criterion prompted a rich exchange of perspectives and uncovered individual assumptions and interpretations. At the group level, type of benefit, disease severity, effectiveness, and quality of evidence favored treatment; cost aspects favored WW (scenario 1). For scenario 2, most criteria did not favor either option., Conclusions: Patients and clinicians consider many aspects in decision-making. The MCDA framework provided a common interpretive frame to structure this complexity, support individual reflection, and share perspectives., Funding: Ipsen Pharma.

Background: The objective of the study was to reveal through pragmatic MCDA (EVIDEM) the contribution of a broad range of criteria to the value of the orphan drug lenvatinib for radioiodine refractory differentiated thyroid cancer (RR-DTC) in country-specific contexts., Methods: The study was designed to enable comprehensive appraisal (12 quantitative, 7 qualitative criteria) in the current disease context (watchful waiting, sorafenib) of France, Italy and Spain. Data on the value of lenvatinib was collected from diverse stakeholders during country-specific panels and included: criteria weights (individual and social values); performance scores (judgments on evidence-collected through MCDA systematic review); qualitative impacts of contextual criteria; and verbal and written insights structured by criteria. The value contribution of each criterion was calculated and uncertainty explored., Results: Comparative effectiveness, Quality of evidence (Spain and Italy) and Disease severity (France) received the greatest weights. Four criteria contributed most to the value of lenvatinib, reflecting its superior Comparative effectiveness (16-22% of value), the severity of RR-DTC (16-22%), significant unmet needs (14-21%) and robust evidence (14-20%). Contributions varied by comparator, country and individuals, highlighting the importance of context and consultation. Results were reproducible at the group level. Impacts of contextual criteria varied across countries reflecting different health systems and cultural backgrounds. The MCDA process promoted sharing stakeholders' knowledge on lenvatinib and insights on context., Conclusions: The value of lenvatinib was consistently positive across diverse therapeutic contexts. MCDA identified the aspects contributing most to value, revealed rich contextual insights, and helped participants express and explicitly tackle ethical trade-offs inherent to balanced appraisal and decisionmaking.

Background: The multiplicity of issues, including uncertainty and ethical dilemmas, and policies involved in appraising interventions for rare diseases suggests that multicriteria decision analysis (MCDA) based on a holistic definition of value is uniquely suited for this purpose. The objective of this study was to analyze and further develop a comprehensive MCDA framework (EVIDEM) to address rare disease issues and policies, while maintaining its applicability across disease areas., Methods: Specific issues and policies for rare diseases were identified through literature review. Ethical and methodological foundations of the EVIDEM framework v3.0 were systematically analyzed from the perspective of these issues, and policies and modifications of the framework were performed accordingly to ensure their integration., Results: Analysis showed that the framework integrates ethical dilemmas and issues inherent to appraising interventions for rare diseases but required further integration of specific aspects. Modification thus included the addition of subcriteria to further differentiate disease severity, disease-specific treatment outcomes, and economic consequences of interventions for rare diseases. Scoring scales were further developed to include negative scales for all comparative criteria. A methodology was established to incorporate context-specific population priorities and policies, such as those for rare diseases, into the quantitative part of the framework. This design allows making more explicit trade-offs between competing ethical positions of fairness (prioritization of those who are worst off), the goal of benefiting as many people as possible, the imperative to help, and wise use of knowledge and resources. It also allows addressing variability in institutional policies regarding prioritization of specific disease areas, in addition to existing uncertainty analysis available from EVIDEM., Conclusion: The adapted framework measures value in its widest sense, while being responsive to rare disease issues and policies. It provides an operationalizable platform to integrate values, competing ethical dilemmas, and uncertainty in appraising healthcare interventions.

Objectives: In 2012, Colombia experienced an important institutional transformation after the establishment of the Health Technology Assessment Institute (IETS), the disbandment of the Regulatory Commission for Health and the reassignment of reimbursement decision-making powers to the Ministry of Health and Social Protection (MoHSP). These dynamic changes provided the opportunity to test Multi-Criteria Decision Analysis (MCDA) for systematic and more transparent resource-allocation decision-making., Methods: During 2012 and 2013, the MCDA framework Evidence and Value: Impact on Decision Making (EVIDEM) was tested in Colombia. This consisted of a preparatory stage in which the investigators conducted literature searches and produced HTA reports for four interventions of interest, followed by a panel session with decision makers. This method was contrasted with a current approach used in Colombia for updating the publicly financed benefits package (POS), where narrative health technology assessment (HTA) reports are presented alongside comprehensive budget impact analyses (BIAs)., Results: Disease severity, size of population, and efficacy ranked at the top among fifteen preselected relevant criteria. MCDA estimates of technologies of interest ranged between 71 to 90 percent of maximum value. The ranking of technologies was sensitive to the methods used. Participants considered that a two-step approach including an MCDA template, complemented by a detailed BIA would be the best approach to assist decision-making in this context. Participants agreed that systematic priority setting should take place in Colombia., Conclusions: This work may serve as the basis to the MoHSP on its interest of setting up a systematic and more transparent process for resource-allocation decision-making.

Background: The diffusion of health technologies from translational research to reimbursement depends on several factors included the results of health economic analysis. Recent research identified several flaws in health economic concepts. Additionally, the heterogeneous viewpoints of participating stakeholders are rarely systematically addressed in current decision-making. Multi-criteria Decision Analysis (MCDA) provides an opportunity to tackle these issues. The objective of this study was to review applications of MCDA methods in decisions addressing the trade-off between costs and benefits., Methods: Using basic steps of the PRISMA guidelines, a systematic review of the healthcare literature was performed to identify original research articles from January 1990 to April 2014. Medline, PubMed, Springer Link and specific journals were searched. Using predefined categories, bibliographic records were systematically extracted regarding the type of policy applications, MCDA methodology, criteria used and their definitions., Results: 22 studies were included in the analysis. 15 studies (68 %) used direct MCDA approaches and seven studies (32 %) used preference elicitation approaches. Four studies (19 %) focused on technologies in the early innovation process. The majority (18 studies - 81 %) examined reimbursement decisions. Decision criteria used in studies were obtained from the literature research and context-specific studies, expert opinions, and group discussions. The number of criteria ranged between three up to 15. The most frequently used criteria were health outcomes (73 %), disease impact (59 %), and implementation of the intervention (40 %). Economic criteria included cost-effectiveness criteria (14 studies, 64 %), and total costs/budget impact of an intervention (eight studies, 36 %). The process of including economic aspects is very different among studies. Some studies directly compare costs with other criteria while some include economic consideration in a second step., Conclusions: In early innovation processes, MCDA can provide information about stakeholder preferences as well as evidence needs in further development. However, only a minority of these studies include economic features due to the limited evidence. The most important economic criterion cost-effectiveness should not be included from a technical perspective as it is already a composite of costs and benefit. There is a significant lack of consensus in methodology employed by the various studies which highlights the need for guidance on application of MCDA at specific phases of an innovation.

Background: Health technology assessment and healthcare decision-making are based on multiple criteria and evidence, and heterogeneous opinions of participating stakeholders. Multi-criteria decision analysis (MCDA) offers a potential framework to systematize this process and take different perspectives into account. The objectives of this study were to explore perspectives and preferences across German stakeholders when appraising healthcare interventions, using multi-criteria assessment of a heart pulmonary sensor as a case study., Methods: An online survey of 100 German healthcare stakeholders was conducted using a comprehensive MCDA framework (EVIDEM V2.2). Participants were asked to provide i) relative weights for each criterion of the framework; ii) performance scores for a health pulmonary sensor, based on available data synthesized for each criterion; and iii) qualitative feedback on the consideration of contextual criteria. Normalized weights and scores were combined using a linear model to calculate a value estimate across different stakeholders. Differences across types of stakeholders were explored., Results: The survey was completed by 54 participants. The most important criteria were efficacy, patient reported outcomes, disease severity, safety, and quality of evidence (relative weight >0.075 each). Compared to all participants, policymakers gave more weight to budget impact and quality of evidence. The quantitative appraisal of a pulmonary heart sensor revealed differences in scoring performance of this intervention at the criteria level between stakeholder groups. The highest value estimate of the sensor reached 0.68 (on a scale of 0 to 1, 1 representing maximum value) for industry representatives and the lowest value of 0.40 was reported for policymakers, compared to 0.48 for all participants. Participants indicated that most qualitative criteria should be considered and their impact on the quantitative appraisal was captured transparently., Conclusions: The study identified important variations in perspectives across German stakeholders when appraising a healthcare intervention and revealed that MCDA can demonstrate the value of a specified technology for all participating stakeholders. Better understanding of these differences at the criteria level, in particular between policymakers and industry representatives, is important to focus innovation aligned with patient health and healthcare system values and constraints.

Background: There is an increased interest in the use of multi-criteria decision analysis (MCDA) to support regulatory and reimbursement decision making. The EVIDEM framework was developed to provide pragmatic multi-criteria decision support in health care, to estimate the value of healthcare interventions, and to aid in priority-setting. The objectives of this study were to test 1) the influence of different weighting techniques on the overall outcome of an MCDA exercise, 2) the discriminative power in weighting different criteria of such techniques, and 3) whether different techniques result in similar weights in weighting the criteria set proposed by the EVIDEM framework., Methods: A sample of 60 Dutch and Canadian students participated in the study. Each student used an online survey to provide weights for 14 criteria with two different techniques: a five-point rating scale and one of the following techniques selected randomly: ranking, point allocation, pairwise comparison and best worst scaling., Results: The results of this study indicate that there is no effect of differences in weights on value estimates at the group level. On an individual level, considerable differences in criteria weights and rank order occur as a result of the weight elicitation method used, and the ability of different techniques to discriminate in criteria importance. Of the five techniques tested, the pair-wise comparison of criteria has the highest ability to discriminate in weights when fourteen criteria are compared., Conclusions: When weights are intended to support group decisions, the choice of elicitation technique has negligible impact on criteria weights and the overall value of an innovation. However, when weights are used to support individual decisions, the choice of elicitation technique influences outcome and studies that use dissimilar techniques cannot be easily compared. Weight elicitation through pairwise comparison of criteria is preferred when taking into account its superior ability to discriminate between criteria and respondents' preferences.

Background: Clostridium difficile infection (CDI) represents a public health problem with increasing incidence and severity., Objective: To evaluate the clinical and economic consequences of vancomycin compared with fidaxomicin in the treatment of CDI from the Canadian health care system perspective., Methods: A decision-tree model was developed to compare vancomycin and fidaxomicin for the treatment of severe CDI. The model assumed identical initial cure rates and included first recurrent episodes of CDI (base case). Treatment of patients presenting with recurrent CDI was examined as an alternative analysis. Costs included were for study medication, physician services and hospitalization. Cost effectiveness was measured as incremental cost per recurrence avoided. Sensitivity analyses of key input parameters were performed., Results: In a cohort of 1000 patients with an initial episode of severe CDI, treatment with fidaxomicin led to 137 fewer recurrences at an incremental cost of $1.81 million, resulting in an incremental cost of $13,202 per recurrence avoided. Among 1000 patients with recurrent CDI, 113 second recurrences were avoided at an incremental cost of $18,190 per second recurrence avoided. Incremental costs per recurrence avoided increased with increasing proportion of cases caused by the NAP1/B1/027 strain. Results were sensitive to variations in recurrence rates and treatment duration but were robust to variations in other parameters., Conclusions: The use of fidaxomicin is associated with a cost increase for the Canadian health care system. Clinical benefits of fidaxomicin compared with vancomycin depend on the proportion of cases caused by the NAP1/B1/027 strain in patients with severe CDI.