METHODS: The guidance document was developed over two face-to-face workshops, in addition to an online survey, a face-to-face interview and pragmatic search of literature. The specific focus was on what, where and how to collect RWD/ RWE.
RESULTS: All 11 REALISE member jurisdictions participated in the online survey and the first in-person workshop, 10 participated in the second in-person workshop, and 8 participated in the in-depth face-to-face interviews. The guidance document was iteratively reviewed by all working group members and the International Advisory Panel. There was substantial variation in: (a) sources and types of RWD being used in HTA, and (b) the relative importance and prioritization of RWE being used for policy-making. A list of national-level databases and other sources of RWD available in each country was compiled. A list of useful guidance on data collection, quality assurance and study design were also compiled.
CONCLUSION: The REALISE guidance document serves to align the collection of better quality RWD and generation of reliable RWE to ultimately inform HTA in Asia.
PATIENTS AND METHODS: This multicenter, randomized, phase III trial evaluated the efficacy and safety of GC followed by EBV-CTL versus GC alone as first-line treatment of R/M NPC patients. Thirty clinical sites in Singapore, Malaysia, Taiwan, Thailand, and the USA were included. Subjects were randomized to first-line GC (four cycles) and EBV-CTL (six cycles) or GC (six cycles) in a 1 : 1 ratio. The primary outcome was overall survival (OS) and secondary outcomes included progression-free survival, objective response rate, clinical benefit rate, quality of life, and safety.
CLINICALTRIALS: gov identifier: NCT02578641.
RESULTS: A total of 330 subjects with NPC were enrolled. Most subjects in both treatment arms received four or more cycles of chemotherapy and most subjects in the GC + EBV-CTL group received two or more infusions of EBV-CTL. The central Good Manufacturing Practices (GMP) facility produced sufficient EBV-CTL for 94% of GC + EBV-CTL subjects. The median OS was 25.0 months in the GC + EBV-CTL group and 24.9 months in the GC group (hazard ratio = 1.19; 95% confidence interval 0.91-1.56; P = 0.194). Only one subject experienced a grade 2 serious adverse event related to EBV-CTL.
CONCLUSIONS: GC + EBV-CTL in subjects with R/M NPC demonstrated a favorable safety profile but no overall improvement in OS versus chemotherapy. This is the largest adoptive T-cell therapy trial reported in solid tumors to date.
DEEPENING INEQUITIES IN A WARMING WORLD: Record temperatures in 2020 resulted in a new high of 3·1 billion more person-days of heatwave exposure among people older than 65 years and 626 million more person-days affecting children younger than 1 year, compared with the annual average for the 1986–2005 baseline (indicator 1.1.2). Looking to 2021, people older than 65 years or younger than 1 year, along with people facing social disadvantages, were the most affected by the record-breaking temperatures of over 40°C in the Pacific Northwest areas of the USA and Canada in June, 2021—an event that would have been almost impossible without human-caused climate change. Although the exact number will not be known for several months, hundreds of people have died prematurely from the heat. Furthermore, populations in countries with low and medium levels of UN-defined human development index (HDI) have had the biggest increase in heat vulnerability during the past 30 years, with risks to their health further exacerbated by the low availability of cooling mechanisms and urban green space (indicators 1.1.1, 2.3.2, and 2.3.3). Agricultural workers in countries with low and medium HDI were among the worst affected by exposure to extreme temperatures, bearing almost half of the 295 billion potential work hours lost due to heat in 2020 (indicator 1.1.4). These lost work hours could have devastating economic consequences to these already vulnerable workers—data in this year’s report shows that the average potential earnings lost in countries in the low HDI group were equivalent to 4–8% of the national gross domestic product (indicator 4.1.3). Through these effects, rising average temperatures, and altered rainfall patterns, climate change is beginning to reverse years of progress in tackling the food and water insecurity that still affects the most underserved populations around the world, denying them an essential aspect of good health. During any given month in 2020, up to 19% of the global land surface was affected by extreme drought; a value that had not exceeded 13% between 1950 and 1999 (indicator 1.2.2). In parallel with drought, warm temperatures are affecting the yield potential of the world’s major staple crops—a 6·0% reduction for maize; 3·0% for winter wheat; 5·4% for soybean; and 1·8% for rice in 2020, relative to 1981–2010 (indicator 1.4.1)—exposing the rising risk of food insecurity. Adding to these health hazards, the changing environmental conditions are also increasing the suitability for the transmission of many water-borne, air-borne, food-borne, and vector-borne pathogens. Although socioeconomic development, public health interventions, and advances in medicine have reduced the global burden of infectious disease transmission, climate change could undermine eradication efforts. The number of months with environmentally suitable conditions for the transmission of malaria (Plasmodium falciparum) rose by 39% from 1950–59 to 2010–19 in densely populated highland areas in the low HDI group, threatening highly disadvantaged populations who were comparatively safer from this disease than those in the lowland areas (indicator 1.3.1). The epidemic potential for dengue virus, Zika virus, and chikungunya virus, which currently primarily affect populations in central America, South America, the Caribbean, Africa, and south Asia, increased globally, with a basic reproductive rate increase of 13% for transmission by Aedes aegypti and 7% for transmission by Aedes albopictus compared with the 1950s. The biggest relative increase in basic reproductive rate of these arboviruses was seen in countries in the very high HDI group (indicator 1.3.1); however, people in the low HDI group are confronted with the highest vulnerability to these arboviruses (indicator 1.3.2). Similar findings are observed in the environmental suitability for Vibrio cholerae, a pathogen estimated to cause almost 100 000 deaths annually, particularly among populations with poor access to safe water and sanitation. Between 2003 and 2019, the coastal areas suitable for V cholerae transmission increased substantially across all HDI country groups—although, with 98% of their coastline suitable to the transmission of V cholerae in 2020, it is people in the low HDI country group that have the highest environmental suitability for this disease (indicator 1.3.1). The concurrent and interconnecting risks posed by extreme weather events, infectious disease transmission, and food, water, and financial insecurity are over-burdening the most vulnerable populations. Through multiple simultaneous and interacting health risks, climate change is threatening to reverse years of progress in public health and sustainable development. Even with overwhelming evidence on the health impacts of climate change, countries are not delivering an adaptation response proportionate to the rising risks their populations face. In 2020, 104 (63%) of 166 countries did not have a high level of implementation of national health emergency frameworks, leaving them unprepared to respond to pandemics and climate-related health emergencies (indicator 2.3.1). Importantly, only 18 (55%) of 33 countries with a low HDI had reported at least a medium level of implementation of national health emergency frameworks, compared with 47 (89%) of 53 countries with a very high HDI. In addition, only 47 (52%) of 91 countries reported having a national adaptation plan for health, with insufficient human and financial resources identified as the main barrier for their implementation (indicator 2.1.1). With a world facing an unavoidable temperature rise, even with the most ambitious climate change mitigation, accelerated adaptation is essential to reduce the vulnerabilities of populations to climate change and protect the health of people around the world.
AN INEQUITABLE RESPONSE FAILS EVERYONE: 10 months into 2021, global and equitable access to the COVID-19 vaccine had not been delivered—more than 60% of people in high-income countries have received at least one dose of a COVID-19 vaccine compared with just 3·5% of people in low-income countries. Data in this report exposes similar inequities in the global climate change mitigation response. To meet the Paris Agreement goals and prevent catastrophic levels of global warming, global greenhouse gas emissions must reduce by half within a decade. However, at the current pace of reduction, it would take more than 150 years for the energy system to fully decarbonise (indicator 3.1), and the unequal response between countries is resulting in an uneven realisation of the health benefits of a low-carbon transition. The use of public funds to subsidise fossil fuels is partly responsible for the slow decarbonisation rate. Of the 84 countries reviewed, 65 were still providing an overall subsidy to fossil fuels in 2018 and, in many cases, subsidies were equivalent to substantial proportions of the national health budget and could have been redirected to deliver net benefits to health and wellbeing. Furthermore, all the 19 countries whose carbon pricing policies outweighed the effect of any fossil fuels subsidies came from the very high HDI group (indicator 4.2.4). Although countries in the very high HDI group have collectively made the most progress in the decarbonisation of the energy system, they are still the main contributors to CO2 emissions through the local production of goods and services, accounting for 45% of the global total (indicator 4.2.5). With a slower pace of decarbonisation and poorer air quality regulations than countries in the very high HDI group, the medium and high HDI country groups produce the most fine particle matter (PM2·5) emissions and have the highest rates of air pollution-related deaths, which are about 50% higher than the total deaths in the very high HDI group (indicator 3.3). The low HDI group, with comparatively lower amounts of industrial activity than in the other groups, has a local production that contributes to only 0·7% of global CO2 emissions, and has the lowest mortality rate from ambient air pollution. However, with only 12% of its inhabitants relying on clean fuels and technologies for cooking, the health of these populations is still at risk from dangerously high concentrations of household air pollution (indicator 3.2). Even in the most affluent countries, people in the most deprived areas over-whelmingly bear the burden of health effects from exposure to air pollution. These findings expose the health costs of the delayed and unequal mitigation response and underscore the millions of deaths to be prevented annually through a low-carbon transition that prioritises the health of all populations. However, the world is not on track to realising the health gains of the transition to a low-carbon economy. Current global decarbonisation commitments are insufficient to meet Paris Agreement ambitions and would lead to a roughly 2·4°C average global temperature increase by the end of the century. The current direction of post-COVID-19 spending is threatening to make this situation worse, with just 18% of all the funds committed for economic recovery from the COVID-19 pandemic by the end of 2020 expected to lead to a reduction of greenhouse gas emissions. Indeed, the economic recovery from the pandemic is already predicted to lead to an unprecedented 5% increase in greenhouse gas emissions in 2021, which will bring global anthropogenic emissions back to their peak amounts. In addition, the current economic recession is threatening to undermine the target of mobilising US$100 billion per year from 2020 onwards to promote low-carbon shifts and adaptation responses in the most underserved countries, even though this quantity is minute compared with the trillions allocated to COVID-19 recovery. The high amounts of borrowing that countries have had to resort to during the pandemic could erase their ability to deliver a green recovery and maximise the health gains to their population of a low-carbon transition.
AN UNPRECEDENTED OPPORTUNITY TO ENSURE A HEALTHY FUTURE FOR ALL: The overshoot in emissions resulting from a carbon-intensive COVID-19 recovery would irreversibly prevent the world from meeting climate commitments and the Sustainable Development Goals and lock humanity into an increasingly extreme and unpredictable environment. Data in this report expose the health impacts and health inequities of the current world at 1·2°C of warming above pre-industrial levels and supports that, on the current trajectory, climate change will become the defining narrative of human health. However, by directing the trillions of dollars that will be committed to COVID-19 recovery towards the WHO’s prescriptions for a healthy, green recovery, the world could meet the Paris Agreement goals, protect the natural systems that support wellbeing, and minimise inequities through reduced health effects and maximised co-benefits of a universal low-carbon transition. Promoting equitable climate change mitigation and universal access to clean energies could prevent millions of deaths annually from reduced exposure to air pollution, healthier diets, and more active lifestyles, and contribute to reducing health inequities globally. This pivotal moment of economic stimulus represents a historical opportunity to secure the health of present and future generations. There is a glimpse of positive change through several promising trends in this year’s data: electricity generation from renewable wind and solar energy increased by an annual average of 17% between 2013 and 2018 (indicator 3.1); investment in new coal capacity decreased by 10% in 2020 (indicator 4.2.1); and the global number of electric vehicles reached 7·2 million in 2019 (indicator 3.4). Additionally, the global pandemic has driven increased engagement in health and climate change across multiple domains in society, with 91 heads of state making the connection in the 2020 UN General Debate and newly widespread engagement among countries in the very high HDI group (indicator 5.4). Whether COVID-19 recovery supports, or reverses these trends, is yet to be seen. Neither COVID-19 nor climate change respect national borders. Without widespread, accessible vaccination across all countries and societies, SARS-CoV-2 and its new variants will continue to put the health of everybody at risk. Likewise, tackling climate change requires all countries to deliver an urgent and coordinated response, with COVID-19 recovery funds allocated to support and ensure a just transition to a low-carbon future and climate change adaptation across the globe. Leaders of the world have an unprecedented opportunity to deliver a future of improved health, reduced inequity, and economic and environmental sustainability. However, this will only be possible if the world acts together to ensure that no person is left behind.
THE IMPACTS OF CLIMATE CHANGE ON HUMAN HEALTH: The world has observed a 1°C temperature rise above pre-industrial levels, with feedback cycles and polar amplification resulting in a rise as high as 3°C in north western Canada., Eight of the ten hottest years on record have occurred in the past decade. Such rapid change is primarily driven by the combustion of fossil fuels, consumed at a rate of 171 000 kg of coal, 116 000 000 L of gas, and 186 000 L of oil per s.– Progress in mitigating this threat is intermittent at best, with carbon dioxide emissions continuing to rise in 2018. Importantly, many of the indicators contained in this report suggest the world is following this “business as usual” pathway. The carbon intensity of the energy system has remained unchanged since 1990 (indicator 3.1.1), and from 2016 to 2018, total primary energy supply from coal increased by 1·7%, reversing a previously recorded downward trend (indicator 3.1.2). Correspondingly, the health-care sector is responsible for about 4·6% of global emissions, a value which is steadily rising across most major economies (indicator 3.6). Global fossil fuel consumption subsidies increased by 50% over the past 3 years, reaching a peak of almost US$430 billion in 2018 (indicator 4.4.1). A child born today will experience a world that is more than four degrees warmer than the pre-industrial average, with climate change impacting human health from infancy and adolescence to adulthood and old age. Across the world, children are among the worst affected by climate change. Downward trends in global yield potential for all major crops tracked since 1960 threaten food production and food security, with infants often the worst affected by the potentially permanent effects of undernutrition (indicator 1.5.1). Children are among the most susceptible to diarrhoeal disease and experience the most severe effects of dengue fever. Trends in climate suitability for disease transmission are particularly concerning, with nine of the ten most suitable years for the transmission of dengue fever on record occurring since 2000 (indicator 1.4.1). Similarly, since an early 1980s baseline, the number of days suitable for Vibrio (a pathogen responsible for part of the burden of diarrhoeal disease) has doubled, and global suitability for coastal Vibrio cholerae has increased by 9·9% indicator 1.4.1). Through adolescence and beyond, air pollution—principally driven by fossil fuels, and exacerbated by climate change—damages the heart, lungs, and every other vital organ. These effects accumulate over time, and into adulthood, with global deaths attributable to ambient fine particulate matter (PM2·5) remaining at 2·9 million in 2016 (indicator 3.3.2) and total global air pollution deaths reaching 7 million. Later in life, families and livelihoods are put at risk from increases in the frequency and severity of extreme weather conditions, with women among the most vulnerable across a range of social and cultural contexts. Globally, 77% of countries experienced an increase in daily population exposure to wildfires from 2001–14 to 2015–18 (indicator 1.2.1). India and China sustained the largest increases, with an increase of over 21 million exposures in India and 17 million exposures in China over this time period. In low-income countries, almost all economic losses from extreme weather events are uninsured, placing a particularly high burden on individuals and households (indicator 4.1). Temperature rise and heatwaves are increasingly limiting the labour capacity of various populations. In 2018, 133·6 billion potential work hours were lost globally, 45 billion more than the 2000 baseline, and southern areas of the USA lost 15–20% of potential daylight work hours during the hottest month of 2018 (indicator 1.1.4). Populations aged 65 years and older are particularly vulnerable to the health effects of climate change, and especially to extremes of heat. From 1990 to 2018, populations in every region have become more vulnerable to heat and heatwaves, with Europe and the Eastern Mediterranean remaining the most vulnerable (indicator 1.1.1). In 2018, these vulnerable populations experienced 220 million heatwave exposures globally, breaking the previous record of 209 million set in 2015 (indicator 1.1.3). Already faced with the challenge of an ageing population, Japan had 32 million heatwave exposures affecting people aged 65 years and older in 2018, the equivalent of almost every person in this age group experiencing a heatwave. Finally, although difficult to quantify, the downstream risks of climate change, such as migration, poverty exacerbation, violent conflict, and mental illness, affect people of all ages and all nationalities. A business as usual trajectory will result in a fundamentally altered world, with the indicators described providing a glimpse of the implications of this pathway. The life of every child born today will be profoundly affected by climate change. Without accelerated intervention, this new era will come to define the health of people at every stage of their lives.
RESPONDING TO CLIMATE CHANGE FOR HEALTH: The Paris Agreement has set a target of “holding the increase in the global average temperature to well below 2°C above pre-industrial levels and pursuing efforts to limit the temperature increase to 1·5°C.” In a world that matches this ambition, a child born today would see the phase-out of all coal in the UK and Canada by their sixth and 11th birthday; they would see France ban the sale of petrol and diesel cars by their 21st birthday; and they would be 31 years old by the time the world reaches net-zero in 2050, with the UK’s recent commitment to reach this goal one of many to come. The changes seen in this alternate pathway could result in cleaner air, safer cities, and more nutritious food, coupled with renewed investment in health systems and vital infrastructure. This second path—which limits the global average temperature rise to “well below 2°C”—is possible, and would transform the health of a child born today for the better, right the way through their life. Considering the evidence available in the 2019 indicators, such a transition could be beginning to unfold. Despite a small increase in coal use in 2018, in key countries such as China, it continued to decrease as a share of electricity generation (indicator 3.1.2). Correspondingly, renewables accounted for 45% of global growth in power generation capacity that year, and low-carbon electricity reached a high of 32% of global electricity in 2016 (indicator 3.1.3). Global per capita use of electric vehicles increased by 20·6% between 2015 and 2016, and now represents 1·8% of China’s total transportation fuel use (indicator 3.4). Improvements in air pollution seen in Europe from 2015 to 2016, could result in a reduction of Years of Life Lost (YLL) worth €5·2 billion annually, if this reduction remained constant across a lifetime (indicator 4.2). In several cases, the economic savings from a healthier and more productive workforce, with fewer health-care expenses, will cover the initial investment costs of these interventions. Similarly, cities and health systems are becoming more resilient to the effects of climate change; about 50% of countries and 69% of cities surveyed reported efforts to conduct national health adaptation plans or climate change risk assessments (indicators 2.1.1, 2.1.2, and 2.1.3). These plans are now being implemented, with the number of countries providing climate services to the health sector increasing from 55 in 2018 to 70 in 2019 (indicator 2.2) and 109 countries reporting medium to high implementation of a national health emergency framework (indicator 2.3.1). Growing demand is coupled with a steady increase in health adaptation spending, which represents 5% (£13 billion) of total adaptation funding in 2018 and has increased by 11·8% over the past 12 months (indicator 2.4). This increase is in part funded by growing revenues from carbon pricing mechanisms, with a 30% increase to US$43 billion in funds raised between 2017 and 2018 (indicator 4.4.3). However, current progress is inadequate, and despite the beginnings of the transition described, the indicators published in the Lancet Countdown’s 2019 report are suggestive of a world struggling to cope with warming that is occurring faster than governments are able, or willing to respond. Opportunities are being missed, with the Green Climate Fund yet to receive projects specifically focused on improving climate-related public health, despite the fact that in other forums, leaders of small island developing states are recognising the links between health and climate change (indicator 5.3). In response, the generation that will be most affected by climate change has led a wave of school strikes across the world. Bold new approaches to policy making, research, and business are needed in order to change course. An unprecedented challenge demands an unprecedented response, and it will take the work of the 7·5 billion people currently alive to ensure that the health of a child born today is not defined by a changing climate.
METHODS: We analyzed the sustained virological response (SVR12) of 15,849 chronic hepatitis C patients from 39 Real-World Evidence from the Asia Liver Consortium for HCV clinical sites in Asia Pacific, North America, and Europe between 07/01/2014-07/01/2021.
RESULTS: The mean age was 62±13 years, with 49.6% male. The demographic breakdown was 91.1% Asian (52.9% Japanese, 25.7% Chinese/Taiwanese, 5.4% Korean, 3.3% Malaysian, and 2.9% Vietnamese), 6.4% White, 1.3% Hispanic/Latino, and 1% Black/African-American. Additionally, 34.8% had cirrhosis, 8.6% had hepatocellular carcinoma (HCC), and 24.9% were treatment-experienced (20.7% with interferon, 4.3% with direct-acting antivirals). The largest group was GT1 (10,246 [64.6%]), followed by GT2 (3,686 [23.2%]), GT3 (1,151 [7.2%]), GT6 (457 [2.8%]), GT4 (47 [0.3%]), GT5 (1 [0.006%]), and untyped GTs (261 [1.6%]). The overall SVR12 was 96.9%, with rates over 95% for GT1/2/3/6 but 91.5% for GT4. SVR12 for GT3 was 95.1% overall, 98.2% for GT3a, and 94.0% for GT3b. SVR12 was 98.3% overall for GT6, lower for patients with cirrhosis and treatment-experienced (TE) (93.8%) but ≥97.5% for treatment-naive patients regardless of cirrhosis status. On multivariable analysis, advanced age, prior treatment failure, cirrhosis, active HCC, and GT3/4 were independent predictors of lower SVR12, while being Asian was a significant predictor of achieving SVR12.
CONCLUSIONS: In this diverse multinational real-world cohort of patients with various GTs, the overall cure rate was 96.9%, despite large numbers of patients with cirrhosis, HCC, TE, and GT3/6. SVR12 for GT3/6 with cirrhosis and TE was lower but still excellent (>91%).