Is it the Right Topic? An Overlooked Stage in the Institutionalization of Health Technology Assessment.

Producing a Health Technology Assessment (HTA) is resource intensive, therefore, an explicit process for Topic Identification, Selection, and Prioritization (TISP) can optimize the use of limited resources to those HTA topics of national importance. TISP does not have to be complicated, however, a formalized process facilitates HTA recommendations that better align with local priorities. The comprehensiveness of TISP processes varies according to countries' needs and to the types of decisions HTA supports. There may be many relevant considerations for TISP, such as the resources available for allocation within the health system, the number of dedicated personnel to complete HTA, and the number of stakeholders and institutions involved in the decision-making process. In countries where HTA-supported decision-making is well-established, the process for TISP is usually formalized. In settings where HTA is emerging, relatively new, or where there may not be the necessary supporting institutional mechanisms, there is limited normative guidance on how to implement TISP. We argue that developing a clear process for TISP is key when institutionalizing HTA. Moreover, insights and experiences from more formalized HTA systems can provide valuable lessons. In this commentary we discuss three institutional aspects that we believe are vital to TISP: 1) Begin topic selection with a clear link to health system feasibility, 2) Ensure legitimacy and impact through transparent TISP processes, and 3) Include the public from the start to embed patient and public engagement throughout HTA.

International Partnerships to Develop Evidence-informed Priority Setting Institutions: Ten Years of Experience from the International Decision Support Initiative (iDSI).

All health systems must set priorities. Evidence-informed priority-setting (EIPS) is a specific form of systematic priority-setting which involves explicit consideration of evidence to determine the healthcare interventions to be provided. The international Decision Support Initiative (iDSI) was established in 2013 as a collaborative platform to catalyze faster progress on EIPS, particularly in low- and middle-income countries. This article summarizes the successes, challenges, and lessons learned from ten years of iDSI partnering with countries to develop EIPS institutions and processes. This is a thematic documentary analysis, structured by iDSI's theory of change, extracting successes, challenges, and lessons from three external evaluations and 19 internal reports to funders. We identified three phases of iDSI's work-inception (2013-15), scale-up (2016-2019), and focus on Africa (2019-2023). iDSI has established a global platform for coordinating EIPS, advanced the field, and supported regional networks in Asia and Africa. It has facilitated progress in securing high-level commitment to EIPS, strengthened EIPS institutions, and developed capacity for health technology assessments. This has resulted in improved decisions on service provision, procurement, and clinical care. Major lessons learned include the importance of sustained political will to develop EIPS; a clear EIPS mandate; inclusive governance structures appropriate to health financing context; politically sensitive and country-led support to EIPS, taking advantage of policy windows for EIPS reforms; regional networks for peer support and long-term sustainability; utilization of context appropriate methods such as adaptive HTA; and crucially, donor-funded global health initiatives supporting and integrating with national EIPS systems, not undermining them.

Considerations for transferability of health technology assessments: a scoping review of tools, methods, and practices.

Health technology assessment (HTA) is commonly used to guide evidence-informed decisions to optimize resource use, prioritize policies, and support countries to achieve universal health coverage. Producing HTAs requires time, scientific expertise, and political commitment, but these are not available in all settings - especially in low- and middle-income countries (LMIC) where HTA processes may be less institutionalized. Transferring and adapting existing HTAs to local settings may offer a solution while reducing duplication efforts. This scoping review aims to provide an overview of tools, methods, approaches, and considerations which can aid HTA transfers. We systematically searched (from 2005 to 2020) six databases and, using predefined inclusion criteria, included twenty-two studies. Data extraction followed a structured process, while synthesis was more iterative. We identified a common approach for HTA transfers. It follows the de novo process of undertaking original HTAs, but with additional steps to assess relevance (applicability), quality, and transferability, as well as steps to adapt parameters where necessary. The EUnetHTA Adaptation Toolkit was the only tool that provided guidance for adapting multiple HTA domains. Other tools were specific to systematic reviews (n = 1) or economic evaluations (n = 12), where one provided guidance for systematic reviews of economic evaluations. Eight papers reported transferring an HTA, with only one transferring to an LMIC. Finally, we reported issues that may facilitate or hinder transferability. In conclusion, we identified fourteen transfer approaches in the form of guidance or checklists, but harmonized and pragmatic guidance for HTA transfers to suit settings with limited HTA capacity seems warranted.

Global access to COVID-19 vaccines: a scoping review of factors that may influence equitable access for low and middle-income countries.

OBJECTIVE: To identify the factors contributing to equitable access to COVID-19 vaccines for low and middle-income countries (LMIC). METHODS: We conducted a scoping review following the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews and a five-stage framework for scoping studies. We performed systematic searches for published peer-reviewed literature in five databases: Medline, Embase, Web of Science, Global Index Medicus and COVID-19 Evidence Epistemonikos (August 2020, updated May 2021). RESULTS: Systematic selection according to predefined criteria resulted in the final inclusion of 45 peer-reviewed articles, with no limitations on study design or publication type. We derived four key factors that potentially influence equitable access to COVID-19 vaccines in LMICs: (1) collectively agreed global mechanisms or frameworks; (2) bilateral purchasing, contracting, and vaccine prices; (3) vaccine manufacturing that is supported by sharing know-how; and (4) countries' strength in implementing vaccination programmes. CONCLUSIONS: This scoping review highlights the ongoing challenges for the international community in ensuring equitable access to COVID-19 vaccines for LMICs. The literature suggests that vaccine manufacturing can influence the supply of vaccines, as can the role of patent holders who can influence global governance through their role in the distribution of COVID-19 vaccines. Our findings indicate that including the principles of equitable access throughout vaccine research and development, procurement, scale-up and distribution processes can support equitable access for LMICs. Advances made with mRNA vaccines may have additional benefits in relation to expanding the manufacturing of other vaccine. Finally, the exploration and scale-up of such capacities of LMICs are likely to prove to be a valuable investment, even after the pandemic.

Developing the HTA core model for the online environment.

BACKGROUND: A framework for collaborative production and sharing of HTA information, the HTA Core Model, was originally developed within EUnetHTA in 2006-08. In this paper, we describe the further development of the Model to allow implementation and utilization of the Model online. The aim was to capture a generic HTA process that would allow effective use of the HTA Core Model and resulting HTA information while at the same time not interfering with HTA agencies' internal processes. METHODS: The work was coordinated by a development team in Finland, supported by an international expert group. Two pilot testing rounds were organized among EUnetHTA agencies and two extensive core HTA projects tested the tool in a real setting. The final work was also formally validated by a group of HTA agencies. RESULTS: The HTA Core Model Online--available at http://www.corehta.info--is a web site hosting a) a tool to allow electronic utilization of the HTA Core Model and b) a database of produced HTA information. While access to the HTA information is free to all, the production features are currently available to EUnetHTA member agencies only. A policy was crafted to steer the use of the Model and produced information. CONCLUSIONS: We have successfully enabled electronic use of the HTA Core Model and agreed on a policy for its utilization. The system is already being used in subsequent HTA projects within EUnetHTA Joint Action 2. Identified shortcomings and further needs will be addressed in subsequent development.

Interaction initiatives between regulatory, health technology assessment and coverage bodies, and industry.

There has been an increased focus on the relationship between health technology assessment (HTA) and regulatory assessments and how regulatory, HTA and coverage bodies, and industry can work better together to improve efficiency and alignment of processes. There is increasingly agreement across sectors that improved communication and coordination could contribute to facilitating timely patient access to effective, affordable treatments that offer value to the health system. Discussions on aspects of this relationship are being held in different forums and various forms of coordination and collaboration are being developed or piloted within several jurisdictions. It is therefore both timely and of value to stakeholders to describe and reflect on current initiatives intended to improve interactions between regulatory, HTA and coverage bodies, and industry. Drawing on 2011 meetings of the HTAi Policy Forum and the Center for Innovation in Regulatory Science (CIRS), this study aims to describe and compare initiatives, and point to success factors and challenges that are likely to inform future work and collaboration.

Interactions between health technology assessment, coverage, and regulatory processes: emerging issues, goals, and opportunities.

BACKGROUND: The relationship between regulatory approval on the one hand and health technology assessment (HTA) and coverage on the other is receiving growing attention. Those responsible for regulatory approval, HTA, and coverage have different missions and their information requirements reflect these. There is nonetheless an increasingly popular view that improved communication and coordination between these functions could allow them all to be undertaken effectively with a lower overall burden of evidence requirements, thus speeding patient access to new products and reducing unnecessary barriers to innovation. This study summarizes the main points emerging from a recent discussion of this topic at the HTAi Policy Forum. RESULTS AND CONCLUSIONS: After considering the roles of the various bodies, stakeholder perspectives and some current practical initiatives, those present at the Forum meeting discussed possible goals and challenges for improved interactions-in general and at specific stages of the product development life cycle. Opportunities for progress were seen in: continuing the dialogue to promote understanding and interaction between the different bodies and stakeholders; working to align scientific advice for manufacturers on the design and data requirements of pre- and post-marketing evaluation of products (specifically phase 2/3 and phase 4 trials for drugs); and extending the current dialogue to include discussion of product development to address unmet health needs.

What principles should govern the use of managed entry agreements?

BACKGROUND: To ensure rapid access to new potentially beneficial health technologies, obtain best value for money, and ensure affordability, healthcare payers are adopting a range of innovative reimbursement approaches that may be called Managed Entry Agreements (MEAs). METHODS: The Health Technology Assessment International (HTAi) Policy Forum sought to identify why MEAs might be used, issues associated with implementation and develop principles for their use. A 2-day deliberative workshop discussed key papers, members' experiences, and collectively addressed four policy questions that resulted in this study. RESULTS: MEAs are used to give access to new technologies where traditional reimbursement is deemed inappropriate. Three different forms of MEAs have been identified: management of budget impact, management of uncertainty relating to clinical and/or cost-effectiveness, and management of utilization to optimize performance. The rationale for using these approaches and their advantages and disadvantages differ. However, all forms of MEA should take the form of a formal written agreement among stakeholders, clearly identifying the rationale for the agreement, aspects to be assessed, methods of data collection and review, and the criteria for ending the agreement. CONCLUSIONS: MEAs should only be used when HTA identifies issues or concerns about key outcomes and/or costs and/or organizational/budget impacts that are material to a reimbursement decision. They provide patient access and can be useful to manage technology diffusion and optimize use. However, they are administratively complex and may be difficult to negotiate and their effectiveness has yet to be evaluated.

Health technology assessment to optimize health technology utilization: using implementation initiatives and monitoring processes.

BACKGROUND: The way in which a health technology is used in any particular health system depends on the decisions and actions of a variety of stakeholders, the local culture, and context. In 2009, the HTAi Policy Forum considered how health technology assessment (HTA) could be improved to optimize the use of technologies (in terms of uptake, change in use, or disinvestment) in such complex systems. METHODS: In scoping, it was agreed to focus on initiatives to implement evidence-based guidance and monitoring activities. A review identified systematic reviews of implementation initiatives and monitoring activities. A two-day deliberative workshop was held to discuss key papers, members' experiences, and collectively address key questions. This consensus paper was developed by email and finalized at a postworkshop meeting. RESULTS: Evidence suggests that the impact and use of HTA could be increased by ensuring timely delivery of relevant reports to clearly determined policy receptor (decision-making) points. To achieve this, the breadth of assessment, implementation initiatives such as incentives and targeted, intelligent dissemination of HTA result, needs to be considered. HTA stakeholders undertake a variety of monitoring activities, which could inform optimal use of a technology. However, the quality of these data varies and is often not submitted to an HTA. CONCLUSIONS: Monitoring data should be sufficiently robust so that they can be used in HTA to inform optimal use of technology. Evidence-based implementation initiatives should be developed for HTA, to better inform decision makers at all levels in a health system about the optimal use of technology.

Phenotype and gene expression of human mesenchymal stem cells in alginate scaffolds.

Human mesenchymal stem cells (MSC) are popular candidates for tissue engineering. MSC are defined by their properties in two-dimensional (2D) culture systems. Cells in 2D are known to differ from their in vivo counterparts in cell shape, proliferation, and gene expression. Little is so far known about the phenotype and gene expression of cells in three-dimensional (3D) culture systems. To begin to unravel the impact of 3D versus 2D culture conditions on MSC, we have established MSC from adipose tissue and bone marrow in 3D cultures in alginate beads covalently modified with the tripeptide arginine-glycine-aspartic acid (RGD), the integrin-binding motif found in several molecules within the extracellular matrix. The MSC changed from their fibroblastoid shape (2D) to a small, compact shape when embedded in RGD alginate (3D). High viability was maintained throughout the experiment. The MSC retained expression of integrins known to bind RGD, and practically ceased to proliferate. Microarray analysis revealed that the gene expression in cells in RGD alginate was different both from the cells cultured in 2D and from prospectively isolated, uncultured MSC, but more similar to 2D cells. As alginate may be entirely dissolved, leaving the cells as single cell suspensions for various analyses, this represents a useful model for the study of cells in 3D cultures.

In vitro expansion of human mesenchymal stem cells: choice of serum is a determinant of cell proliferation, differentiation, gene expression, and transcriptome stability.

Human bone marrow mesenchymal stem cells (hMSCs) represent an appealing source of adult stem cells for cell therapy and tissue engineering, as they are easily obtained and expanded while maintaining their multilineage differentiation potential. All current protocols for in vitro culture of hMSCs include fetal bovine serum (FBS) as nutritional supplement. FBS is an undesirable additive to cells that are expanded for therapeutic purposes in humans because the use of FBS carries the risk of transmitting viral and prion diseases and proteins that may initiate xenogeneic immune responses. In the present study, we have therefore investigated if autologous serum (AS) or allogeneic human serum (alloHS) could replace FBS for the expansion of hMSCs in vitro. We discovered that the choice of serum affected hMSCs at several different levels. First, hMSCs in AS proliferated markedly faster than hMSCs in FBS, whereas use of alloHS resulted in hMSC growth arrest and death. Second, hMSCs in FBS differentiated more rapidly toward mesenchymal lineages compared with hMSCs in AS. Interestingly, genome-wide microarray analysis identified several transcripts involved in cell cycle and differentiation that were differentially regulated between hMSCs in FBS and AS. Finally, several transcripts, including some involved in cell cycle inhibition, were upregulated in hMSCs in FBS at a late passage, whereas the hMSC transcriptome in AS was remarkably stable. Thus, hMSCs may be expanded rapidly and with stable gene expression in AS in the absence of growth factors, whereas FBS induces a more differentiated and less stable transcriptional profile.

Isolation and transcription profiling of purified uncultured human stromal stem cells: alteration of gene expression after in vitro cell culture.

Stromal stem cells proliferate in vitro and may be differentiated along several lineages. Freshly isolated, these cells have been too few or insufficiently pure to be thoroughly characterized. Here, we have isolated two populations of CD45-CD34+CD105+ cells from human adipose tissue which could be separated based on expression of CD31. Compared with CD31+ cells, CD31- cells overexpressed transcripts associated with cell cycle quiescence and stemness, and transcripts involved in the biology of cartilage, bone, fat, muscle, and neural tissues. In contrast, CD31+ cells overexpressed transcripts associated with endothelium and the major histocompatibility complex class II complex. Clones of CD31- cells could be expanded in vitro and differentiated into cells with characteristics of bone, fat, and neural-like tissue. On culture, transcripts associated with cell cycle quiescence, stemness, certain cytokines and organ specific genes were down-regulated, whereas transcripts associated with signal transduction, cell adhesion, and cytoskeletal +CD105+CD31- cells from human adipose tissue have stromal stem cell properties which may make them useful for tissue engineering.

Histone deacetylase inhibitors differentially mediate apoptosis in prostate cancer cells.

BACKGROUND: Histone deacetylase (HDAC) inhibitors have shown significant anti-proliferative and apoptotic properties on various cancer cells, including prostate cancer, and are therefore being evaluated as treatment modalities. However, the specific effect of HDAC inhibitors on androgen-sensitive and androgen-independent cell lines have not been thoroughly studied which we hypothesized could be different. We therefore assessed whether three structurally unrelated HDAC inhibitors, trichostatin A (TSA), depsipeptide (FR901228), and sodium butyrate, affect cell death in the prostate cancer cell lines LNCaP, DU-145, and PC-3. METHODS: To investigate the extent and the nature of cell death, we used Trypan blue exclusion assay, phase-contrast light microscopy, fluorescence microscopy, and Western blot analyses. RESULTS: At concentrations where they potentiate transcriptional activation, all three HDAC inhibitors induced cell death in LNCaP and DU-145 cells, but not in PC-3 cells, within the timeline of the experiments. HDAC inhibitor-induced cell death in LNCaP and DU-145 cells showed several characteristic apoptotic features, such as cell shrinkage, nuclear condensation, and poly(ADP) ribose polymerase cleavage. However, there were differences in the way LNCaP and DU-145 cells responded to treatment with various HDAC inhibitors. For example, whereas TSA and FR901228 were more effective in inducing apoptosis in LNCaP cells compared with DU-145 cells, the reverse was true for sodium butyrate. Moreover, within the same cell line, TSA, FR901228, and sodium butyrate exhibited different potencies for induction of apoptosis. CONCLUSIONS: Collectively, these results suggest that the response of prostate cancer cells to HDAC inhibitors is not uniform, but cell line and inhibitor specific. Given that prostate cancer is generally a multiclonal disease representing different cell lineages, it is important to develop HDAC inhibitors that will be effective against all of these cell types.