HOW CAN HEALTH SYSTEMS PREPARE FOR NEW AND EMERGING HEALTH TECHNOLOGIES? THE ROLE OF HORIZON SCANNING REVISITED.

OBJECTIVES: For many years, several health technology assessment (HTA) agencies scanned the horizon to identify health technologies that were safe, effective and offer value for money. However, there is limited evidence regarding its impact. The role of horizon scanning in preparing health systems for the uptake of new and emerging health technologies was discussed during the 2018 HTA International (HTAi) Global Policy Forum Meeting. METHODS: Reflection of the discussion between seventy-two senior representatives from for-profit, not-for-profit organizations, and HTAi leadership. It was informed by a background paper, and presentations from four invited experts and seventeen Policy Forum members. RESULTS: Current horizon scanning systems (HSS) mainly identify health technologies in the late stage of development, aiming to inform topic selection for HTA. Areas for improvement included the need for a clearer definition of the end user(s), purpose, scope, and focus of HSS, the long-term full health system effects, including all relevant stakeholders as early as possible, and considering smart data systems and international collaboration to improve HSS's efficiency. The way in which HSS could be further optimized and better shaped to prepare health systems was also discussed and good practice examples were presented. CONCLUSIONS: HSS have not yet reached their full potential in preparing health systems. To improve the current situation, the HTA community could act as convenors, bringing together all relevant stakeholders and providing the information that decision makers need. This would require a new, more integrative approach to define and use HSS and HTA, and requires new skills.

DEVELOPMENTS IN VALUE FRAMEWORKS TO INFORM THE ALLOCATION OF HEALTHCARE RESOURCES.

BACKGROUND: In recent years, there has been a surge in the development of frameworks to assess the value of different types of health technologies to inform healthcare resource allocation. The reasons for, and the potential of, these value frameworks were discussed during the 2017 Health Technology Assessment International (HTAi) Policy Forum Meeting. METHODS: This study reflects the discussion, drawing on presentations from invited experts and Policy Forum members, as well as a background paper. RESULTS: The reasons given for a proliferation of value frameworks included: rising healthcare costs; more complex health technology; perceived disconnect between price and value in some cases; changes in societal values; the need for inclusion of additional considerations, such as ethical issues; and greater empowerment of clinicians and patients in defining and using value frameworks. Many Policy Forum participants recommended learning from existing frameworks. Furthermore, there was a desire to agree on the core components of value frameworks, defining the additional value elements as necessary and considering how they might be measured and used in practice. Furthermore, adherence to the principles of transparency, predictability, broad stakeholder involvement, and accountability were widely supported, along with being forward looking, explicit, and consistent across decisions. CONCLUSIONS: Value frameworks continue to evolve with significant implications for global incentives for innovation and access to health technologies. There is a role for the HTA community to address some of the key areas discussed during the meeting, such as defining the core components for assessing the value of a health technology.

The completeness of intervention descriptions in published National Institute of Health Research HTA-funded trials: a cross-sectional study.

OBJECTIVES: The objective of this study was to assess whether National Institute of Health Research (NIHR) Health Technology Assessment (HTA)-funded randomised controlled trials (RCTs) published in the HTA journal were described in sufficient detail to replicate in practice. SETTING: RCTs published in the HTA journal. PARTICIPANTS: 98 RCTs published in the HTA journal up to March 2011. Completeness of the intervention description was assessed independently by two researchers using a checklist, which included assessments of participants, intensity, schedule, materials and settings. Disagreements in scoring were discussed in the team; differences were then explored and resolved. PRIMARY AND SECONDARY OUTCOME MEASURES: Proportion of trials rated as having a complete description of the intervention (primary outcome measure). The proportion of drug trials versus psychological and non-drug trials rated as having a complete description of the intervention (secondary outcome measures). RESULTS: Components of the intervention description were missing in 68/98 (69.4%) reports. Baseline characteristics and descriptions of settings had the highest levels of completeness with over 90% of reports complete. Reports were less complete on patient information with 58.2% of the journals having an adequate description. When looking at individual intervention types, drug intervention descriptions were more complete than non-drug interventions with 33.3% and 30.6% levels of completeness, respectively, although this was not significant statistically. Only 27.3% of RCTs with psychological interventions were deemed to be complete, although again these differences were not significant statistically. CONCLUSIONS: Ensuring the replicability of study interventions is an essential part of adding value in research. All those publishing clinical trial data need to ensure transparency and completeness in the reporting of interventions to ensure that study interventions can be replicated.

The first biologically active synthetic analogues of FK228, the depsipeptide histone deacetylase inhibitor.

The FK228 and spiruchostatin bicyclic depsipeptide natural products are among the most potent histone deacetylase (HDAC) inhibitors known. Although FK228 is in advanced clinical trials, the complexity of the natural products has precluded mechanistic studies and the discovery of structure-activity relationships. By total synthesis, we have prepared the first depsipeptide analogues. Our results prove that the dehydrobutyrine residue in FK228 is not essential, and other residues can be substituted without loss of HDAC inhibitory activity. Conformational restriction by the macrocyclic scaffold is important, as a linear peptide was inactive. The intramolecular disulfide formed with a cysteine side chain can be removed provided the zinc-binding thiol is protected to ensure good cellular availability. Like the natural products, the analogues are selective against class I isoforms, with nanomolar inhibition of class I HDAC1 and significantly less potency against class II HDAC6.

Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage.

Enforced expression of the antiapoptotic Bcl-2 family protein Mcl-1 promotes lymphomagenesis in the mouse; however, the functional role of Mcl-1 in human B-cell lymphoma remains unclear. We demonstrate that Mcl-1 is widely expressed in malignant B-cells, and high-level expression of Mcl-1 is required for B-lymphoma cell survival, since transfection of Mcl-1-specific antisense oligodeoxynucleotides was sufficient to promote apoptosis in Akata6 lymphoma cells. Mcl-1 was efficiently cleaved by caspases at evolutionarily conserved aspartic acid residues in vitro, and during cisplatin-induced apoptosis in B-lymphoma cell lines and spontaneous apoptosis of primary malignant B-cells. Overexpression of the Mcl-1 cleavage product that accumulated during apoptosis was sufficient to kill cells. Therefore, Mcl-1 is an essential survival molecule for B-lymphoma cells and is cleaved by caspases to a death-promoting molecule during apoptosis. In contrast to Mcl-1, Bcl-2 and Bcl-XL were relatively resistant to caspase cleavage in vitro and in intact cells. Interfering with Mcl-1 function appears to be an effective means of inducing apoptosis in Mcl-1-positive B-cell lymphoma, and the unique sensitivity of Mcl-1 to caspase-mediated cleavage suggests an attractive strategy for converting it to a proapoptotic molecule.

Total synthesis of spiruchostatin A, a potent histone deacetylase inhibitor.

The total synthesis of spiruchostatin A was accomplished, unambiguously confirming its structure. Key steps included the use of the Nagao thiazolidinethione auxiliary for a diastereoselective acetate aldol reaction and as an activated acylating agent for amide formation, and macrolactonization by the Yamaguchi protocol. Spiruchostatin A is shown to have biological activity similar to that of FK228, a potent histone deacetylase (HDAC) inhibitor in clinical trials. The spiruchostatin A analogue, epimeric at the beta-hydroxy acid, is inactive, highlighting the importance of stereochemistry at this position for interactions with HDACs.