Capturing the value of vaccination within health technology assessment and health economics: Literature review and novel conceptual framework.

BACKGROUND: Vaccination provides significant health gains to individuals and society and can potentially improve health equity, healthcare systems and national economies. Policy decisions, however, are rarely informed by comprehensive economic evaluations (EE) including vaccination's wide-ranging value. The objective of this analysis was to focus on health technology assessment systems to identify relevant value concepts in order to improve current EE of non-pandemic vaccines. METHODS: Following a literature review, a novel Value of Vaccination (VoV) framework was developed with experts in vaccine EE from developed countries with established health technology assessment systems. RESULTS: Forty-four studies presenting value frameworks or concepts applicable to vaccination were included. Eighteen unique value concepts relevant to EE were identified and defined. These were categorised within the VoV framework using three dimensions, moving from a narrow payer perspective to a more expansive and societal perspective. The dimensions were: (I) conventional payer perspective concepts (e.g., health gains in vaccinees, direct medical costs); (II) conventional societal perspective concepts (e.g., indirect health/economic gains to caregivers/households, productivity in vaccinees); and (III) novel societal concepts (e.g., financial risk protection, peace of mind, societal health gains, healthcare systems security, political stability, social equity and macroeconomic gains). While good quality evidence and methods are available to support concepts in Dimensions I and II, further work is needed to generate the required evidence for vaccination impact on Dimension III concepts. CONCLUSIONS: The devastating effect on nations of the COVID-19 pandemic has helped to highlight the potential far-reaching benefits that many vaccination programmes can offer. This VoV framework is particularly relevant to policy decisions considering EE, and the potential future expansion of non-pandemic vaccination value considerations. The framework helps to understand and compare current value considerations across countries and payer versus societal perspectives. It provides decision-makers with a transparent and logical path to broaden consideration of VoV in EE.

Impact of the COVID-19 pandemic on the conduct of clinical trials: a quantitative analysis.

Background: Globally, healthcare has shouldered much of the socioeconomic brunt of the COVID-19 pandemic leading to numerous clinical trials suspended or discontinued. Objective: To estimate the COVID-19 impact on the number of clinical trials worldwide. Methods: Data deposited by 219 countries in the ClinicalTrials.gov database (2007-2020) were interrogated using targeted queries. A time series model was fitted to the data for studies ongoing, initiated, or ended between 2007 Quarter (Q) 1 and 2019 Q4 to predict the expected trials number in 2020 in the COVID-19 absence. The predicted values were compared with the actual 2020 data to quantify the pandemic impact. Results: The ongoing registered trials number grew from 2007 Q1 (33,739) to 2019 Q4 (80,319). By contrast, there were markedly fewer ongoing trials in all four quarters of 2020 compared with forecasted values (1.6%-2.8% decrease). When excluding COVID-19-related studies, this disparity grew further (3.4%-5.8% decrease), to a peak of almost 5,000 fewer ongoing trials than estimated for 2020 Q2. The initiated non-COVID-19 trials number was higher than predicted in 2020 Q4 (9.9%). Conclusions: This pandemic has impacted clinical trials. Provided that current trends persist, clinical trial activities may soon recover to at least pre-COVID-19 levels.

Capturing the value of vaccination within health technology assessment and health economics: Country analysis and priority value concepts.

BACKGROUND: A value of vaccination framework for economic evaluation (EE) identified unique value concepts for the broad benefits vaccination provides to individuals, society, healthcare systems and national economies. The objectives of this paper were to work with experts in developed countries to objectively identify three priority concepts to extend current EE. METHODS: The previously developed classification of value concepts in vaccination distinguished 18 concepts, categorised as conventional payer and societal perspective concepts and novel broader societal concepts. Their inclusion in current EE guidelines was assessed. Experts identified eight criteria relevant to decision-making and measurement feasibility, which were weighted and used to score each concept. The relative ranking of concepts by importance and the gaps in guidelines were used to identify three priority concepts on which to focus immediate efforts to extend EE. RESULTS: The EE guidelines review highlighted differences across countries and between guidelines and practice. Conventional payer perspective concepts (e.g., individual and societal health gains and medical costs) were generally included, while gaps were evident for conventional societal perspective concepts (e.g., family/caregiver health and economic gains). Few novel broader societal benefits were considered, and only in ad hoc cases. The top-three concepts for near-term consideration: macroeconomic gains (e.g., benefiting the economy, tourism), social equity and ethics (e.g., equal distribution of health outcomes, reduced health/financial equity gaps) and health systems strengthening, resilience and security (e.g., efficiency gains, reduced disruption, increased capacity). CONCLUSIONS: Gaps, inconsistencies and limited assessment of vaccination value in EE can lead to differences in policy and vaccination access. The three priority concepts identified provide a feasible approach for capturing VoV more broadly in the near-term. Robust methods for measuring and valuing these concepts in future assessments will help strengthen the evidence used to inform decisions, improving access to vaccines that are demonstrably good value for money from society's point of view.

A systematic literature review of revealed preferences of decision-makers for recommendations of cancer drugs in health technology assessment.

OBJECTIVES: This review intends to provide an overview of revealed preferences of decision-makers for recommendations of cancer drugs in health technology assessment (HTA) among the different agencies. METHODS: A systematic literature search was performed in MEDLINE and EMBASE databases from inception to July 2020. The studies were eligible for inclusion if they conducted a quantitative analysis of HTA's previous decisions for cancer drugs. The factors with p-values below the significance level of .05 were considered as the statistically significant factors for HTA decisions. RESULTS: A total of nine studies for six agencies in Australia, Belgium, France, South Korea, the UK, and Canada were eligible to be included. From the univariable analysis, improvements in clinical outcomes and cost-effectiveness were found as significant factors for the agencies in Belgium, South Korea, and Canada. From the multivariable analysis, cost-effectiveness was found as a positive factor for the agencies in the UK, South Korea, and Canada. Few factors related to characteristics of disease and technology were found to be significant among the included agencies. CONCLUSIONS: Despite the different drug reimbursement systems and the socioeconomic situations, cost-effectiveness and/or improvement on clinical outcomes seemed to be the most important factors for recommendations of cancer drugs among the agencies.

On the association between SARS-COV-2 variants and COVID-19 mortality during the second wave of the pandemic in Europe.

OBJECTIVE: This study aims at investigating associations between COVID-19 mortality and SARS-COV-2 variants spread during the second wave of COVID-19 pandemic in Europe. METHODS: For 38 European countries, data on numbers of COVID-19 deaths, SARS-COV-2 variants spread through time using Nextstrain classification, demographic and health characteristics were collected. Cumulative number of COVID-19 deaths and height of COVID-19 daily deaths peak during the second wave of the pandemic were considered as outcomes. Pearson correlations and multivariate generalized linear models with selection algorithms were used. RESULTS: The average proportion of B.1.1.7 variant was found to be a significant predictor of cumulative COVID-19 deaths within two months before the peak and between 1 January-25 February 2021, as well as of the deaths peak height considering proportions during the second wave and the pre-peak period. The average proportion of EU2 variant (S:477 N) was a significant predictor of cumulative COVID-19 deaths in the pre-peak period. CONCLUSIONS: Our findings suggest that spread of a new variant of concern B.1.1.7 had a significant impact on mortality during the second wave of COVID-19 pandemic in Europe and that proportions of EU2 and B.1.1.7 variants were associated with increased mortality in the initial phase of that wave.

The real-life impact of vaccination on COVID-19 mortality in Europe and Israel.

OBJECTIVES: This study aimed at estimating the real-life impact of vaccination on COVID-19 mortality, with adjustment for SARS-CoV-2 variants spread and other factors across Europe and Israel. STUDY DESIGN: Time series analysis. METHODS: Time series analysis of the daily number of COVID-19 deaths was performed using non-linear Poisson mixed regression models. Variables such as variants' frequency, demographics, climate, health, and mobility characteristics of thirty-two countries between January 2020 and April 2021 were considered as potentially relevant adjustment factors. RESULTS: The analysis revealed that vaccination efficacy in terms of protection against deaths was 72%, with a lower reduction of the number of deaths for B.1.1.7 vs non-B.1.1.7 variants (70% and 78%, respectively). Other factors significantly related to mortality were arrivals at airports, mobility change from the prepandemic level, and temperature. CONCLUSIONS: Our study confirms a strong effectiveness of COVID-19 vaccination based on real-life public data, although lower than expected from clinical trials. This suggests the absence of indirect protection for non-vaccinated individuals. Results also show that vaccination effectiveness against mortality associated with the B.1.1.7 variant is slightly lower than that with other variants. Lastly, this analysis confirms the role of mobility reduction, within and between countries, as an effective way to reduce COVID-19 mortality and suggests the possibility of seasonal variations in COVID-19 incidence.

Vaccine market access pathways in the EU27 and the United Kingdom - analysis and recommendations for improvements.

BACKGROUND: Vaccine market access (VMA) pathways across the European Union (EU) and the United Kingdom (UK) are complex, lengthy, and heterogeneous, particularly when compared with pharmaceuticals. The knowledge base to inform recommendations for optimization of VMA is lacking. We therefore conducted a comprehensive evaluation of EU VMA pathways. METHODS: Research in two phases included: (1) mapping VMA pathways in each EU member state (including the UK) based on a literature review, expert interviews, and mathematical archetyping; and (2) interviews with vaccine experts to identify barriers, drivers, and recommendations for regional VMA alignments. RESULTS: Key steps in VMA across the EU include horizon scanning, early advice, National Immunization Technical Advisory Group (NITAG) recommendation for inclusion in national immunization programs, health technology assessment (HTA), final decision and procurement. We found significant complexity and heterogeneity, particularly for early advice, and in the roles, decision-making criteria, and transparency of NITAGs and HTA bodies. The most important drivers for rapid VMA included demonstration of disease burden and vaccine benefit (e.g., efficacy, safety, economic). Key barriers were budget limitations and complexity/clarity of VMA processes (e.g., need for national-regional consensus, clarity on process initiation, and clarity on the role of HTA). Recommendations for alignment at EU and member-state levels include information sharing, joint clinical assessment, initiatives to address funding and political barriers, and improved transparency by decision-making bodies. Early engagement with vaccine stakeholders was a key recommendation for manufacturers. CONCLUSIONS: There is significant potential for alignment, collaboration, and improvement of VMA across the EU. Roles, responsibilities, and transparency of key bodies can be clarified. The COVID-19 pandemic response should stimulate policies to improve access to all vaccines, including routine ones, and form the foundation upon which a consistent vaccine ecosystem can be created for the EU, one that is resilient, consistent between member states, and fit for purpose.

The impact of COVID-19 on the cell and gene therapies industry: Disruptions, opportunities, and future prospects.

Coronavirus 2019 (COVID-19) has caused significant disruption to the cell and gene therapy (CGT) industry, which has historically faced substantial complexities in supply of materials, and manufacturing and logistics processes. As decision-makers shifted their priorities to COVID-19-related issues, the challenges in market authorisation, and price and reimbursement of CGTs were amplified. Nevertheless, it is encouraging to see that some CGT developers are adapting their efforts toward the development of promising COVID-19-related therapeutics and vaccines. Manufacturing resilience, digitalisation, telemedicine, value-based pricing, and innovative payment mechanisms will be increasingly harnessed to ensure that market access of CGTs is not severely disrupted.

Factors influencing the COVID-19 daily deaths' peak across European countries.

OBJECTIVES: The purpose of this study was to determine predictors of the height of coronavirus disease 2019 (COVID-19) daily deaths' peak and time to the peak, to explain their variability across European countries. STUDY DESIGN: For 34 European countries, publicly available data were collected on daily numbers of COVID-19 deaths, population size, healthcare capacity, government restrictions and their timing, tourism and change in mobility during the pandemic. METHODS: Univariate and multivariate generalised linear models using different selection algorithms (forward, backward, stepwise and genetic algorithm) were analysed with height of COVID-19 daily deaths' peak and time to the peak as dependent variables. RESULTS: The proportion of the population living in urban areas, mobility at the day of first reported death and number of infections when borders were closed were assessed as significant predictors of the height of COVID-19 daily deaths' peak. Testing the model with a variety of selection algorithms provided consistent results. Total hospital bed capacity, population size, the number of foreign travellers and the day of border closure were found to be significant predictors of time to COVID-19 daily deaths' peak. CONCLUSIONS: Our analysis demonstrated that countries with higher proportions of the population living in urban areas, countries with lower reduction in mobility at the beginning of the pandemic and countries having more infected people when closing borders experienced a higher peak of COVID-19 deaths. Greater bed capacity, bigger population size and later border closure could result in delaying time to reach the deaths' peak, whereas a high number of foreign travellers could accelerate it.

A critical analysis and review of Lancet COVID-19 hydroxychloroquine study.

Purpose A international registry analysis led by Mehra et al. to investigate the use of hydroxychloroquine (HCQ) and chloroquine (CQ) with or without a macrolide in 96,032 hospitalised COVID-19 patients were published on Lancet, which has raised considerable discussions in the public health community. This study aimed to critically review the quality and limitations of the Mehra et al. publication and discuss the potential influences on the use of HCQ/CQ worldwide. Method A critical review of this publication was conducted to examine the potential study bias in the study objectives, methodology, confounding factors and outcomes and summarise the external reviews. Results The very high homogeneity of the patients' characteristics at baseline was inconsistent with region specific epidemiology and several critical confounding factors. The results indicated that angiotensin converting enzyme inhibitors were associated with a hazard ratio of 0.5, which suggested a technical problem in the estimation of the propensity scores. Several major risk factors for mortality identified in the analysis were treated as a minor risk or neutral or even protective factors. Antiviral treatments were recognised as an effective method to reduce mortality and were neither further studied nor integrated in the multivariate Cox model. Conclusion This research appeared to carry multiple biases. An extensive audit of the study, conditions of review and acceptance for publication in the Lancet of that study are requested to avoid damage to the publics' trust on the scientific community at this critical time of COVID-19 pandemic.

Chinese guidelines related to novel coronavirus pneumonia.

Background and Objective: China has managed to control the coronavirus disease (COVID-19) with confinement measurements and treatment strategies, while other countries are struggling to contain the spread. This study discusses the guidelines related to COVID-19 in China in order to provide important references for other countries in the fight against COVID-19. Methods: Chinese guidelines relevant to COVID-19 were systematically searched via the China National Knowledge Infrastructure database, YiMaiTong database, and World Health Organization (WHO) COVID-19 database on March 20th, 2020. Guideline information was extracted, including date of publication, source, objectives and the target population. Guidelines specific to the pharmacological treatment of COVID-19 were further investigated to identify the types of antivirus drugs recommended and to report on how treatment recommendations for COVID-19 have evolved overtime. Results: A total of 100 guidelines were identified, of which 74 were national guidelines and 26 were regional guidelines. The scope of included guidelines consisted of: the diagnosis and treatment of COVID-19, the management of hospital departments and specific diseases during the outbreak of COVID-19. Fifty-one of the included guidelines targeted overall COVID-19 patients, while the remaining guidelines concentrated on special patient populations (i.e. geriatric population, pediatric population, and pregnant population) or patients with coexisting diseases. Fifteen guidelines focused on the pharmacological treatments for all COVID-19 patients. Interferon, Lopinavir/Ritonavir, Ribavirin, Chloroquine, and Umifenovir represented the most recommended antivirus drugs. Among them, 7 Chinese guidelines have recommended Chloroquine Phosphate or Hydroxychloroquine for the treatment of COVID-19. Conclusions: China has generated a plethora of guidelines covering almost all aspects of COVID-19. Chloroquine, as one widely affordable treatment, was recommended by Chinese national guidelines and provincial guidelines. Considering the continuous debates around Chloroquine, confirmatory studies with robust methodology are awaited to address the unanswered questions on its potential benefits and risks on COVID-19.

Commentary on "Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open label non-randomized clinical trial" by Gautret et al.

The results of a clinical trial comparing hydroxychloroquine with or without azithromycin to the standard of care for the treatment of COVID-19 were recently published by Philippe Gautret et al. This study provides outstanding results for the combination of hydroxychloroquine and azithromycin over the standard of care, but the evidence was deemed insufficiently robust to warrant a public health decision to widen the use of hydroxychloroquine for the treatment of COVID-19. We provide a scientific critical review of the Gautret et al. publication, put the results in the context of the current knowledge, provide an evaluation of the validity of the results (from a methodologic perspective), and discuss public health implications. The study has a number of limitations, including small sample size, lack of comparability between patients in active treatment and control arms, lack of blinding, use of interim analyses without controlling for the risk of type 1 error, use of analysis in the per-protocol population instead of the intention-to-treat population, and inconsistencies between the study protocol and article. However, none of these observations is of a nature to reverse the conclusions. The study brings useful knowledge consistent with available evidence and clinical practice from China and South Korea, which could have prompted quicker policy decision-making.