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.

The fourth edition of the European Network for Health Technology Assessment Forum: highlights and outcomes.

The European Network for Health Technology Assessment (EUnetHTA) organizes an annual Forum with stakeholders to receive feedback on its activities, processes, and outputs produced. The fourth edition of the EUnetHTA Forum brought together representatives of HTA bodies, patient organizations, healthcare professionals (HCPs), academia, payers, regulators, and industry. The aim of this paper is to provide an overview of the highlights presented at the 2019 EUnetHTA Forum, reporting the main items and themes discussed in the plenary panel and breakout sessions. The leading topic was the concept of unmet medical need seen from different stakeholders' perspectives. Breakout sessions covered the joint production of assessment reports and engagement with payers, patients, and HCPs. Synergies, pragmatism, and inclusiveness across Member States and stakeholders were emphasized as leading factors to put in place a collaboration that serves the interest of patients and public health in a truly European spirit.

Multiple treatment comparison of seven new drugs for patients with advanced malignant melanoma: a systematic review and health economic decision model in a Norwegian setting.

OBJECTIVE: To assess the relative effectiveness and cost-effectiveness of seven new drugs (cobimetinib, dabrafenib, ipilimumab, nivolumab, pembrolizumab, trametinib and vemurafenib) used for treatment of patients with advanced malignant melanoma in the Norwegian setting. DESIGN: A multiple technology assessment. PATIENTS: Patients with advanced malignant melanoma aged 18 or older. DATA SOURCES: A systematic search for randomised controlled trials in relevant bibliographic databases. METHODS: We performed network meta-analyses using both direct and indirect evidence with dacarbazine as a common comparator. We ranked the different treatments in terms of their likelihood of leading to the best results for each endpoint. The cost-utility analysis was based on a probabilistic discrete-time Markov cohort model. The model calculated the costs and quality-adjusted life years (QALYs) with different treatment strategies from a healthcare perspective. Sensitivity analysis was performed by means of Monte Carlo simulation. RESULTS: Monotherapies with a programmed cell death 1 (PD-1) immune-checkpoint-inhibitor had a higher probability of good performance for overall survival than monotherapies with ipilimumab or BRAF/MEK inhibitors. The combination treatments had all similar levels of effectiveness to the PD-1 immune-checkpoint-inhibitors.PD-1 immune-checkpoint-inhibitors are more effective and more costly compared with ipilimumab in monotherapy. Nivolumab in combination with ipilimumab had higher costs and the same level of effectiveness as the PD-1 immune-checkpoint-inhibitors in monotherapy.BRAF/MEK inhibitor combinations (dabrafenib and trametinib or vemurafenib and cobimetinib) had both similar effectiveness and cost-effectiveness; however, the combination therapies are more likely to give higher quality adjusted life year gains than BRAF or MEK inhibitor monotherapies, but to a higher cost. CONCLUSIONS: None of the drugs investigated can be considered cost-effective at what has normally been considered a reasonable willingness-to-pay (WTP) in Norway. Price reductions (from the official list prices) in the region of 63%-84% would be necessary for these drugs to be cost-effective at a WTP of €55 850 per QALY.

Interventions aimed at communities to inform and/or educate about early childhood vaccination.

BACKGROUND: A range of strategies are used to communicate with parents, caregivers and communities regarding child vaccination in order to inform decisions and improve vaccination uptake. These strategies include interventions in which information is aimed at larger groups in the community, for instance at public meetings, through radio or through leaflets. This is one of two reviews on communication interventions for childhood vaccination. The companion review focuses on face-to-face interventions for informing or educating parents. OBJECTIVES: To assess the effects of interventions aimed at communities to inform and/or educate people about vaccination in children six years and younger. SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE and five other databases up to July 2012. We searched for grey literature in the Grey Literature Report and OpenGrey. We also contacted authors of included studies and experts in the field. There were no language, date or settings restrictions. SELECTION CRITERIA: Individual or cluster-randomised and quasi-randomised controlled trials, interrupted time series (ITS) and repeated measures studies, and controlled before-and-after (CBA) studies. We included interventions aimed at communities and intended to inform and/or educate about vaccination in children six years and younger, conducted in any setting. We defined interventions aimed at communities as those directed at a geographic area, and/or interventions directed to groups of people who share at least one common social or cultural characteristic. Primary outcomes were: knowledge among participants of vaccines or vaccine-preventable diseases and of vaccine service delivery; child immunisation status; and unintended adverse effects. Secondary outcomes were: participants' attitudes towards vaccination; involvement in decision-making regarding vaccination; confidence in the decision made; and resource use or cost of intervention. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the references to identify studies for inclusion. We extracted data and assessed risk of bias in all included studies. MAIN RESULTS: We included two cluster-randomised trials that compared interventions aimed at communities to routine immunisation practices. In one study from India, families, teachers, children and village leaders were encouraged to attend information meetings where they received information about childhood vaccination and could ask questions. In the second study from Pakistan, people who were considered to be trusted in the community were invited to meetings to discuss vaccine coverage rates in their community and the costs and benefits of childhood vaccination. They were asked to develop local action plans and to share the information they had been given and continue the discussions in their communities.The trials show low certainty evidence that interventions aimed at communities to inform and educate about childhood vaccination may improve knowledge of vaccines or vaccine-preventable diseases among intervention participants (adjusted mean difference 0.121, 95% confidence interval (CI) 0.055 to 0.189). These interventions probably increase the number of children who are vaccinated. The study from India showed that the intervention probably increased the number of children who received vaccinations (risk ratio (RR) 1.67, 95% CI 1.21 to 2.31; moderate certainty evidence). The study from Pakistan showed that there is probably an increase in the uptake of both measles (RR 1.63, 95% CI 1.03 to 2.58) and DPT (diptheria, pertussis and tetanus) (RR 2.17, 95% CI 1.43 to 3.29) vaccines (both moderate certainty evidence), but there may be little or no difference in the number of children who received polio vaccine (RR 1.01, 95% CI 0.97 to 1.05; low certainty evidence). There is also low certainty evidence that these interventions may change attitudes in favour of vaccination among parents with young children (adjusted mean difference 0.054, 95% CI 0.013 to 0.105), but they may make little or no difference to the involvement of mothers in decision-making regarding childhood vaccination (adjusted mean difference 0.043, 95% CI -0.009 to 0.097).The studies did not assess knowledge among participants of vaccine service delivery; participant confidence in the vaccination decision; intervention costs; or any unintended harms as a consequence of the intervention. We did not identify any studies that compared interventions aimed at communities to inform and/or educate with interventions directed to individual parents or caregivers, or studies that compared two interventions aimed at communities to inform and/or educate about childhood vaccination. AUTHORS' CONCLUSIONS: This review provides limited evidence that interventions aimed at communities to inform and educate about early childhood vaccination may improve attitudes towards vaccination and probably increase vaccination uptake under some circumstances. However, some of these interventions may be resource intensive when implemented on a large scale and further rigorous evaluations are needed. These interventions may achieve most benefit when targeted to areas or groups that have low childhood vaccination rates.'

HPV catch-up vaccination of young women: a systematic review and meta-analysis.

BACKGROUND: While prophylactic human papilloma virus (HPV) vaccination is considered effective in young girls, it is unclear whether a catch-up vaccination of older girls would be beneficial. We, therefore, aimed to examine the potential health impact of a HPV catch-up vaccination of girls who were too old at the time of vaccine introduction, hence aged 16 and older. METHODS: We systematically searched the literature for randomized clinical trials (RCTs) that examined the effect of HPV vaccines on overall mortality, cancer mortality and incidence, high-grade cervical intraepithelial neoplasia grade 2 and higher (CIN2+), vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VaIN) grade 2 and higher lesions (VIN2+ and VaIN2+, respectively) genital warts (condyloma). We considered all lesions and those associated with HPV type(s) included in the vaccines. RCTs reporting on serious adverse events were also eligible. Selected publications were assessed for potential risk of bias, and we ascertained the overall quality of the evidence for each outcome using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Meta-analyses were performed, assuming both random and fixed effects, to estimate risk ratios (RR) and corresponding 95% confidence intervals (CI), using intention-to-treat and per-protocol populations. RESULTS: We included 46 publications reporting on 13 RCTs. Most of the RCTs had a maximum follow-up period of four years. We identified no RCT reporting on the effect of HPV catch vaccination on overall and cancer related mortality, and on cervical cancer incidence. We found a borderline protective effect of a HPV catch-up vaccination on all CIN2+, with a pooled RR of 0.80 (95% CI: 0.62-1.02) for a follow-up period of 4 years. A HPV catch-up vaccination was associated with a reduction in VIN2+ and VaIN2+ lesions, and condyloma. No difference in risk of serious adverse events was seen in vaccinated participants versus unvaccinated women (pooled RR of 0.99 (0.91-1.08)). CONCLUSIONS: This systematic review indicates that a HPV catch-up vaccination could be beneficial, however the long-term effect of such a vaccination, and its effect on cervical cancer incidence and mortality is still unclear.

Antivirals for influenza: a summary of a systematic review and meta-analysis of observational studies.

Despite the use of antivirals to treat patients with severe influenza, questions remain with respect to effects and safety. Although a recent systematic review has provided some indication of benefit, the analysis is limited by the quality of the available evidence from randomized controlled trials. To supplement the existing information, the authors conducted a systematic review of observational studies of antiviral treatment for influenza. This report summarises the findings of that review. Similar to the randomised trials, the confidence in the estimates of the effects for decision-making is low to very low primarily due to the risk of selection and publication bias in the observational studies. From these observational studies, the summary estimates suggest that oseltamivir may reduce mortality, hospitalisation and duration of symptoms compared with no treatment. Inhaled zanamivir may also reduce symptom duration and hospitalisations, but patients may experience more complications compared with no treatment. Earlier treatment with antivirals is generally associated with better outcomes than later treatment. Further high-quality evidence is needed to inform treatment guidelines because of the overall low to very low quality of evidence.

Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies.

BACKGROUND: Systematic reviews of randomized, controlled trials in patients with influenza suggest a lack of evidence about the effects of antiviral therapy on several patient-important outcomes of influenza. PURPOSE: To systematically review observational studies for benefits and harms of oseltamivir, zanamivir, amantadine, or rimantadine in the treatment of influenza. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL, SIGLE, the Chinese Biomedical Literature Database, Panteleimon, and LILACS up to November 2010; contact with pharmaceutical companies; and reference lists. STUDY SELECTION: Observational studies in any language that compared single antiviral therapy with no therapy or other antiviral therapy, or that had no comparator, for influenza or influenza-like illness. DATA EXTRACTION: Two independent investigators extracted data. Confidence in the estimates of the obtained effects (quality of evidence) was assessed by using the Grading of Recommendations Assessment, Development, and Evaluation approach. DATA SYNTHESIS: 74 studies fulfilled the inclusion criteria. Meta-analyses of the few studies providing effects with adjustment for confounders suggest that, in high-risk populations, oral oseltamivir may reduce mortality (odds ratio, 0.23 [95% CI, 0.13 to 0.43]; low-quality evidence), hospitalization (odds ratio, 0.75 [CI, 0.66 to 0.89]; low-quality evidence), and duration of symptoms (33 hours [CI, 21 to 45 hours]; very low-quality evidence) compared with no treatment. Earlier treatment with oseltamivir was generally associated with better outcomes. Inhaled zanamivir may lead to shorter symptom duration (23 hours [CI, 17 to 28 hours]; moderate-quality evidence) and fewer hospitalizations (odds ratio, 0.66 [CI, 0.37 to 1.18]) but more complications than no treatment. Direct comparison of oral oseltamivir and inhaled zanamivir suggests no important differences in key outcomes. Data from 1 study suggest that oral amantadine may reduce mortality and pneumonia associated with influenza A. No included study evaluated rimantadine. LIMITATIONS: Mortality was assessed in high-risk patients, and generalizability is limited. The overall body of evidence is limited by risk for confounding and selection, reporting, and publication bias. CONCLUSION: Therapy with oral oseltamivir and inhaled zanamivir may provide a net benefit over no treatment of influenza. However, as with the randomized trials, the confidence in the estimates of the effects for decision making is low to very low. PRIMARY FUNDING SOURCES: World Health Organization and McMaster University.

Cochrane summary of findings: horse chestnut seed extract for chronic venous insufficiency.

As part of its efforts to disseminate the results of Cochrane reviews to a wider audience, the Cochrane Complementary and Alternative Medicine (CAM) Field develops Summary of Findings (SoF) tables and then uses these tables as a basis for its Plain Language Summaries. In each SoF table, the most important outcomes of the review, the effect of the intervention on each outcome, and the quality of the evidence for each outcome are presented. The process of developing the SoF table involves deciding which outcomes to present for which time points and evaluating the strength and quality of the evidence for the outcomes. The Cochrane CAM Field contacted the authors of this review to request clarification on any points that are not understood in the Cochrane review and also to request their review of the SoF. In this article, review authors in the Cochrane Collaboration reviewed the effects of horse chestnut seed extract for chronic venous insufficiency.

The effect of probiotics for preventing acute upper respiratory tract infections.

As part of its efforts to disseminate the results of Cochrane reviews to a wider audience, the Cochrane Complementary and Alternative Medicine (CAM) Field develops Summary of Findings (SoF) tables and then uses those tables as a basis for its plain-language summaries. Each SoF table presents the most important outcomes for the review as well as the effect of the intervention and the quality of the evidence for each outcome. The process of developing the SoF table involves deciding which outcomes to present for which time points and evaluating the strength and quality of the evidence for the outcomes. In this article, we present a Cochrane review about the effects of the use of probiotics for preventing acute upper respiratory tract infections. We contacted the authors of the Cochrane review to request clarification on points that we did not understand and to have them review the SoF table.

HLA-A3 restricted mutant ras specific cytotoxic T-lymphocytes induced by vaccination with T-helper epitopes.

Cytotoxic T-lymphocytes are one of the most important elements of the antitumor defense. Stimulation of cytotoxic T-lymphocytes outgrowth after immunization with mutant ras peptides is a desired goal since these cells may kill tumor cells in vivo. In this study we tested responding peripheral mononuclear cells from a patient with pancreatic adenocarcinoma who had received intradermal peptide vaccination with a mixture of 17-mer mutant ras peptides and granulocyte-macrophage colony-stimulating factor as an adjuvant. Responding peripheral T-cells were cloned by limiting dilution and several CD8(+) cytotoxic T-lymphocytes, specific for the K- RAS 12-Cys mutation were obtained. By using a panel of nonamer peptides containing the 12-Cys mutation and covering position 4-21 in the ras molecule, the 9-mer peptide which was actually recognized by the cytotoxic T-lymphocytes could be identified. HLA-A*0302 could be identified as the antigen-presenting molecule, and the amino acid sequence of the T-cell epitope carries the previously identified HLA-A*0302 binding motif. The nonamer peptide was contained within the vaccine peptide originally used for intradermal immunization of the patient. The cytotoxic T-lymphocytes were capable of killing target cells expressing HLA-A*0302 that coexpressed the K- RAS 12-Cys mutation after transfection. These data demonstrate that the peptide used for vaccination (17-mer) is processed and presented in vivo, and that generation of cytotoxic T-lymphocytes by vaccination with T-helper epitopes may be important for further development of specific immunotherapy of cancer patients.