key: cord-262143-s01jrtbb authors: Head, Michael G; Brown, Rebecca J; Newell, Marie-Louise; Scott, J Anthony G; Batchelor, James; Atun, Rifat title: The allocation of US$105 billion in global funding from G20 countries for infectious disease research between 2000 and 2017: a content analysis of investments date: 2020-09-21 journal: Lancet Glob Health DOI: 10.1016/s2214-109x(20)30357-0 sha: doc_id: 262143 cord_uid: s01jrtbb BACKGROUND: Each year, billions of US$ are spent globally on infectious disease research and development. However, there is little systematic tracking of global research and development. We present research on investments into infectious diseases research from funders in the G20 countries across an 18-year time period spanning 2000–17, comparing amounts invested for different conditions and considering the global burden of disease to identify potential areas of relative underfunding. METHODS: The study examined research awards made between 2000 and 2017 for infectious disease research from G20-based public and philanthropic funders. We searched research databases using a range of keywords, and open access data were extracted from funder websites. Awards were categorised by type of science, specialty, and disease or pathogen. Data collected included study title, abstract, award amount, funder, and year. We used descriptive statistics and Spearman's correlation coefficient to investigate the association between research investment and disease burden, using Global Burden of Disease 2017 study data. FINDINGS: The final 2000–17 dataset included 94 074 awards for infectious disease research, with a sum investment of $104·9 billion (annual range 4·1 billion to 8·4 billion) and a median award size of $257 176 (IQR 62 562–770 661). Pre-clinical research received $61·1 billion (58·2%) across 70 337 (74·8%) awards and public health research received $29·5 billion (28·1%) from 19 197 (20·4%) awards. HIV/AIDS received $42·1 billion (40·1%), tuberculosis received $7·0 billion (6·7%), malaria received $5·6 billion (5·3%), and pneumonia received $3·5 billion (3·3%). Funding for Ebola virus ($1·2 billion), Zika virus ($0·3 billion), influenza ($4·4 billion), and coronavirus ($0·5 billion) was typically highest soon after a high-profile outbreak. There was a general increase in year-on-year investment in infectious disease research between 2000 and 2006, with a decline between 2007 and 2017. Funders based in the USA provided $81·6 billion (77·8%). Based on funding per 2017 disability-adjusted life years (DALYs), HIV/AIDS received the greatest relative investment ($772 per DALY), compared with tuberculosis ($156 per DALY), malaria ($125 per DALY), and pneumonia ($33 per DALY). Syphilis and scabies received the least relative investment (both $9 per DALY). We observed weak positive correlation (r=0·30) between investment and 2017 disease burden. INTERPRETATION: HIV research received the highest amount of investment relative to DALY burden. Scabies and syphilis received the lowest relative funding. Investments for high-threat pathogens (eg, Ebola virus and coronavirus) were often reactive and followed outbreaks. We found little evidence that funding is proactively guided by global burden or pandemic risk. Our findings show how research investments are allocated and how this relates to disease burden and diseases with pandemic potential. FUNDING: Bill & Melinda Gates Foundation. Large amounts of funding are allocated to research in infectious diseases each year, 1 spanning pre-clinical science, clinical trials, product development, and public health, including implementation research. These allocations involve numerous stakeholders across the global health community, including funders, researchers, policy makers, and clinicians. However, there is little systematic tracking or detailed analysis of investments into research and development for infectious diseases to support how to make the best funding decisions. 2 Nor is there systematic coordination between stakeholders involved in funding research and development, despite efforts such as the WHO Global Observatory on Health R&D to achieve better coordination. 1 Funders differ in their approaches to commissioning research, from the curiosity-driven approaches of the Wellcome Trust, 3 to the focused data-driven strategies of the Bill & Melinda Gates Foundation, 4 which creates a heterogeneous landscape of research priorities. Thus, there is a need for an in-depth and comprehensive review of the global research and development landscape to identify what research has taken place, where the research was done, and which institutions were involved in the research. Such research on research is crucial for priority setting, informing funding decisions, and improving efficiency in allocating funds. 2 We present research done by the Research Investments in Global Health (RESIN) Study Group on research investments into infectious diseases from funders in the G20 countries across an 18-year time period spanning 2000-17, comparing amounts invested for different conditions and considering the global burden of disease to identify potential areas of relative underfunding. This study considered research awards related to infectious disease research from 987 public and philanthropic funders in the G20 countries (appendix p 2), made between Jan 1, 2000, and Dec 31, 2017. The methods used were similar to those described in detail elsewhere. [5] [6] [7] [8] Data collected included study title, abstract, award amount, funder, and year. Data were manually collated from multiple sources. Awards to institutions in the UK between Jan 1, 1997, and Dec 31, 2013, have been previously analysed. 7, 8 Most data (>90%) from 2016 and 2017 were sourced from the UberResearch Dimensions database, which includes 4·9 million financial awards across health and nonhealth research and development sectors from 501 global funders. US National Institutes of Health (NIH) data from between Jan 1, 2000 and Dec 31, 2015, was sourced directly from the Project Reporter database. Other data were sourced from the websites of individual funders, funder databases such as the World Report, the UK National Research Register (a now-archived website owned by the UK Department of Health), or by contacting the funder directly and requesting data. We applied keyword searches and filters (appendix p 2) to identify studies of human-related infectious disease. Awards purely focused on plant pathology or veterinary science were excluded, unless there was a clear zoonotic component. Excluded studies were manually reviewed to identify any false negatives. The included financial awards were individually scrutinised to assess their relevance to infection. MGH assessed all financial awards for inclusion and categorised infection-related awards, applying keyword labels as appropriate (appendix pp 2-3). Secondary checks on included and excluded awards were made (by RJB and other), as per the study protocol. 7,8 15 000 (15·9%) of 94 074 awards were double checked, with a review of the award inclusion in the dataset and the applied labels indicating the disease areas of the research. Where there was disagreement, study information was provided to a third co-author for consensus. Research award amounts were adjusted for inflation in original currency and converted to 2017 US$ using the mean exchange rate in the award year. Award amounts were missing for 6072 (5·7%) of 94 074 awards, from 13 funders (appendix p 2). In these cases, estimates To our knowledge, this is the first study to describe in depth the global landscape for all infectious disease research from public and philanthropic funders. Our study covers 18 years of funding data, so captures long-term time trends and fluctuations. We combined and categorised awards using the classification system developed by the ResIn study. This strategy allowed us to provide a comprehensive overview of how infectious disease funding has been allocated, and compare findings with the global burden of disease, an important variable to consider when setting research priorities. This information can be used by global health research funders in decision-making processes. Our findings show that between 2000 and 2017, HIV received significantly more research funding than similar high-burden diseases such as tuberculosis, malaria, and pneumonia. The USA provides much of the global funding, particularly the US National Institute for Health. There are several infections that appear neglected compared with their burden of disease, such as syphilis and scabies. Thus, the global health community could use our findings to inform discussions, alongside other drivers for research prioritisation. were made using maximum award amounts for that funding stream as per the funder's website, by asking principal investigators for an approximate or exact award amount provided, or by asking in-country researchers who had knowledge of the research and development landscape for typical award amounts. Datasets and analyses were circulated to all authors for review and comment. Included award types comprised project and programme grants, fellowships, and pump-priming or pilot projects. Excluded award types were conference and infrastructure grants and funding focused on operational activities rather than research. Labels applied to each award included pathogen, disease areas and specialty (eg, antimicrobial resistance, respiratory, oncology, and paediatrics), and type of science along the research continuum (pre-clinical, phase 1-3 clinical trials, phase 4 and product development research, public health [ focusing on populations], and cross-disciplinary studies across multiple stages of the research continuum). We defined cross-disciplinary as a study that covered more than one stage of the research continuum (for example pre-clinical research that progressed to a phase 1 study). Antimicrobial resistance included antibacterial, antiviral, antiparasitic, and antifungal resistance. The diagnostics category included research into screening. Sexually-transmitted infections excluded HIV, which had its own category. Neglected tropical diseases were based on the WHO definition (as of Oct 23, 2019). 9 Burden of disease data were sourced from the Global Burden of Disease study online tool. 10 Disease burden data are reported from 2017 for all infectious diseases, and additional examples are presented using HIV/ AIDS, malaria, tuberculosis, and pneumonia from years 2005 and 2011 (six-year time intervals during the period covered by the investments dataset). Measures of disease burden analysed were mortality, disabilityadjusted life years (DALYs), and years lived with disability (YLD). Comparison between awards and their associated observed disease burden were made by calculating investment per mortality, DALY, or YLD observed. We computed the investment relative to the burden of infection using the following equation: cumulative research investment up to the year of burden measure or number of deaths, DALYs, or YLD at that timepoint. For example, for assessment of HIV DALYs in 2017, the sum of HIV research investment from Jan 1, 2000, to Dec 31, 2017 ($42·1 billion), was divided by DALYs in 2017 (54 446 184), to get an investment per DALY metric of $772. Descriptive statistics and Spearman's correlation coefficient were used to investigate the relationship between research investment and disease burden, using Global Burden of Disease 2017 study data. We used Microsoft Excel 2016 for data preparation Stata SE version 16 for data analysis. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The HIV/AIDS was the pathogen or disease with the greatest amount of funding ($42·1 billion [40·1%]) across 21 403 (22·8%) awards (tables 1, 2). Funding for tuberculosis totalled $7·0 billion (6·7%) from 5246 (5·6%) awards, funding for malaria was $5·6 billion (5·3%) from 4437 (4·3%) awards, and funding for pneumonia was $3·5 billion (3·3%) from 2748 (2·9%) awards. Funding for Ebola virus-related research was $1·2 billion (1·1%); $0·8 billion (68·0%) of all Ebola virus-related research investment was awarded between 2014 and 2017, following the high-profile outbreak of Ebola virus disease in West Africa in 2014. 11 Similarly, $0·3 billion of funding was allocated to research on Zika virus, of which 96·0% was awarded in 2016 or 2017 after the Zika virus epidemic. 12 Of the $4·4 billion (4·2%) of funding for influenza, $2·0 billion (45·0%) was awarded in 2006-10, with the highest annual funding amount awarded in 2009 ($0·6 billion [12·8%]). There were global outbreaks of H1N1 influenza in 2005 (so-called bird flu) and 2009 (so-called swine flu). 11 Funding for coronavirus-related research was $0·5 billion (0·5%) from 396 (0·4%) grants, with a median award size of $2·0 million (IQR 0·6 million to 2·9 million; , the year after the international SARS outbreak, 13 By disease area, $3·8 billion (3·6%) was awarded for antimicrobial resistance from 4845 (5·2%) awards, $4·1 billion (3·9%) was awarded for neglected tropical diseases, $1·1 billion (1·0%) for sepsis, and $1·4 billion (1·3%) for health-care-associated infections. In areas relating to hard-to-reach groups, $2·0 billion (1·9%) was awarded for infections related to drug use and addiction and $0·2 billion (0·2%) for infectious diseases in prison (table 1) . Awards for comorbidities and non-communicable diseases included $0·3 billion (0·3%) for mental health and $0·6 billion (0·6%) for cardiovascular disease. Funders from the USA provided $81·6 billion (77·8%) of the investment, which covered 42 926 (45·6%) of the awards. Within this, the US NIH was the largest funder, providing $59·4 billion (56·6% of total US funding) and the greatest number of individual awards (32 967 [35·0%]). The Bill & Melinda Gates Foundation provided $9·2 billion (8·8%) in 2317 (2·5%) awards. UK funders provided $8·3 billion (7·9%) in 8358 (8·9%) awards. When the awards had a clear geographical focus, $9·2 billion (8·8%) of the funding was focused on Africa and $2·4 billion (2·3%) on Asia (appendix p 2). When ranking investment levels on the basis of burden of disease by DALYs across 34 infectious diseases (appendix p 2), African trypanosomiasis ($9740 per DALY) and genital herpes ($3101 per DALY) were ranked first and second, respectively (table 2). HIV/AIDS ($772 per DALY) was ranked eighth, tuberculosis ($156 per DALY) was ranked seventeenth, malaria ($125 per DALY) was ranked twenty first, enteric infections ($68 per DALY) were ranked twenty fourth, and pneumonia ($33 per DALY) was ranked twenty eighth. Scabies and syphilis were ranked joint last with $9 per DALY. When comparing investment for individual infections alongside 2017 DALYs, Spearman's correlation coefficient was 0·30 (p=0·048), suggesting weak positive correlation between research investment and global burden of disease ( figure 2) . Infections within the shaded area of the graph showed a stronger correlation between investment and burden of disease. Infections below the shaded area were relatively underinvested, and infections above the shaded area were relatively well-invested, compared with their 2017 DALYs burden. When comparing investment by mortality, syphilis ($632 per death) and tetanus ($749 per death) were ranked the lowest of the 27 infections for which mortality data were available (appendix p 2). The highest-ranked infections by investment per death were those for which associated mortality is typically low, specifically chlamydia ($712 076 per death) and African trypanosomiasis ($563 094 per death). HIV was ranked seventh ($44 481 per death), malaria was ranked thirteenth ($9107 per death), tuberculosis was ranked fifteenth ($5936 per death), and pneumonia was ranked twenty fourth ($1392 per death). Across different timepoints of the study, HIV-related research consistently received greater investment than did malaria, tuberculosis, or pneumonia (figure 3). Pneumonia-related research consistently received far less funding during the study period compared with HIV, tuberculosis, or malaria. By type of science, 35·5% of research funding for HIV was for pre-clinical research, 15·1% for phase 1-3 trials, and 45·9% for public health research (appendix p 9). Pneumonia had the greatest proportion of funding allocated to pre-clinical science (55·7%) and the lowest amount for public health research (23·5%) compared with HIV, tuberculosis, and malaria (appendix p 2). In this study, we provide an analysis of $105 billion of research investment as 94 074 public and philanthropic awards for infectious disease research covering the years 2000-17. Over half of this investment was for pre-clinical science and over a quarter for public health research. By type of infection, HIV-related research received more than double the investment for tuberculosis, malaria, and pneumonia combined. Infections that are relatively less well-funded include some sexually-transmitted infections (syphilis and gonorrhoea) and neglected skin infections, such as scabies. Funding for coronavirus-related research was $0·5 billion from 396 grants, of which 95·1% was for preclinical research. However, in 2020 there has been a huge reactive effort to support the response to the COVID-19 pandemic, which includes substantial financing for research. 15 As of Aug 4, 2020, the RESIN study has tracked $1·6 billion of global public and philanthropic research funding, which already exceeds the 2017 total investment in HIV research ($1·1 billion; appendix page 2). Viral respiratory infections are known to be one of the most likely causes of a pandemic, but despite this and the existing high levels of mortality in young children and older people due to such infections, systems for pneumonia research and advocacy are not well established. 16 Confusion over the definition of pneumonia, 17 few experienced researchers to make a strong case to funders, and few high-profile public figures championing the cause have led to pitifully low levels of funding compared with the disease burden. The Bill & Melinda Gates Foundation, which is guided by childhood deaths, is the main funder of pneumonia-related research. 5 The metrics used to compare investment by burden of disease are misleading for pathogens such as Ebola virus and Zika virus, which at first appear to be relatively wellfunded compared with their burden of disease (appendix p 2). However, for these conditions, which are public health emergencies, DALYs are not a fair metric to use. Outbreaks of this nature are not necessarily high-burden in terms of numbers of cases but are high-risk given the potential for rapid spread to cause widespread outbreaks, an important factor that influences research investment decisions. As illustrated by the evolving COVID-19 pandemic, there is a public health need to support outbreak responses and research should very much be part of such a response. Such outbreaks create uncertainty and fear, with media promoting a need to do something and urging political circles to respond rapidly. 18, 19 Historical funding for coronavirus research was very low, even after the high-profile outbreaks of severe acute respiratory syndrome (SARS), due to SARS coronavirus, and Middle East respiratory syndrome and the potential for the rapid spread of such infections. 20 Other analyses highlight how funding for neglected infectious disease research (distinct from neglected tropical diseases) is increasing. 21 Our analysis supports this conclusion, for example, showing that research on neglected tropical diseases or with a focus on Africa is increasing (appendix p 2). There have been substantial declines in HIV funding, primarily in higher-income settings (and thus not captured under neglected disease definitions). The Coalition for Epidemic Preparedness Innovations, founded in 2016, has received substantial research investment from multiple funders to research selected high-threat pathogens. 22 For example, there are several ongoing studies to develop a universal influenza vaccine to reduce pandemic risk, as well as vaccine in development against coronaviruses. 23 Antimicrobial resistance, which continues to be a serious worldwide threat, 24 has led to the introduction of the Global AMR R&D Hub with a remit to address challenges and improve coordination and collaboration in global antimicrobial resistance research and development using a One Health approach. 25 Antimicrobial resistance is also an important contributor to sepsis mortality, which is responsible for 11 million deaths annually with most of the burden in sub-Saharan Africa, 26 but receives just 1·0% of the funding. Research investment analyses can be a valuable audit of a system that has perhaps maximised scientific efficiency through peer review of curiosity driven research and provide a direction for revision of research on under-investigated diseases and subject-based opportunities. The COVID-19 pandemic has shown the fragility of national and global infrastructures, and pandemic preparedness will surely be a focus for highprofile global health research stakeholders in years to come. Sustainable tracking of how research funding is spent is vital to ensure that all priority areas and knowledge gaps are addressed, 15 and there must be adequate translation of that new knowledge into policy and practice, with findings that can be feasibly adopted in resource-poor settings. Multiple factors other than the current and projected burden of disease influence research funding decisions, such as political drivers of decision making (notable in our study given the major funder was the US Government), advocacy and lobbying, emergency preparedness for emerging infectious diseases with pandemic potential, and public health research for conflicts and other humanitarian responses. Applying a globally recognised label to a disease can be important. WHO oversees the designated list of neglected tropical diseases, 9 which helps to raise the profile of these conditions and support arguments for research funding. 27 As an example, African trypano somiasis, which has been at the forefront of efforts to tackle neglected tropical diseases, has been described as an extraordinary success story, with a decline in the DALY burden by 93% between 2000 and 2017. 28 African trypanosomiasis has received twice the amount of research funding compared with lymphatic filariasis or schistosomiasis, and more than non-neglected tropical diseases, such as meningitis or the respiratory syncytial virus. Researchers who study African trypanosomiasis have elimination and eradication in sight, although this will probably require further substantial investments. 28 Investment in other neglected areas might help produce similar effective responses, although the type of research investment must be appropriate. For example, our analysis highlighted scabies and syphilis as particularly underfunded. Effective treatments are available for scabies, so the most useful research might be around an effective drug supply chain or addressing stigma. Other factors beyond the burden of disease also influence the direction and amount of investment. The geographic focus of research investments affects the likelihood of knowledge being translated into policy and practice, particularly in the country or sector where the research was undertaken. 29 It is important to consider where research capacity should be created or enhanced, rather than simply which research areas to prioritise and fund. The UK invests greater resources in former colonies, influenced by historical ties and a shared language. 30 Investments in different sectors will also be affected by diplomatic considerations, for example, funding countries seeking cooperation from recipient countries or regions in response to security threats and terrorism. This study has several limitations. There will be missing data, particularly when data could not be accessed from public and philanthropic funders. We propose that the effect of this should not be substantial and should not greatly influence our findings, as the included data relate to 18 of the top 20 leading investors in research. 31, 32 The focus on G20 countries means that funders from countries who are not in this group but are proactive in global health research, such as Switzerland and Norway, were not included. A key challenge was integrating data that were presented in numerous different formats. Future analyses would be simplified considerably if funders could adopt a minimum dataset of required information, perhaps recommended by the WHO Global Observatory on Health R&D, which would require that applicants add standard labels (eg, the type of science along the research pipeline) to their project at time of submission. Applying categories to an award retrospectively is time-consuming and subjective, although errors were reduced by observations from a second author and consensus. Automated categorisation based on keyword searches is problematic, since the title and abstract of many awards contain references to diseases that are not the study areas of focus. Furthermore, separating out awards for operational or implementation research and activities that are nonresearch based implementation (ie, not generating new knowledge) is a subjective process. Our study lacks data from the private sector, particularly concerning tools and products such as vaccines, diagnostics, and therapeutics. The analyses use Global Burden of Disease study data, which are themselves modelled estimates and will on occasions be based on imputations due to missing data, and have been subject to criticism. 33 Selection of timepoints for research investments and disease burden will affect our findings as both of these change over time. More than $100 billion has been spent globally on infectious disease research between 2000 and 2017, but this funding does not correlate with current levels of burden or the level of risk posed by infections with pandemic potential. Since priority setting for research must consider many different factors, our analysis should be used to support decision making rather than providing clear-cut answers. It is worrying that the funding allocated to infectious disease research is declining during a period in which there are concerns surrounding antimicrobial resistance and the pandemic potential of many pathogens. In conclusion, our findings show where research funding resources are allocated and how this relates to disease burden and diseases with pandemic potential. We anticipate that our results could be an invaluable resource to global health stakeholders (eg, WHO, research funders, or national governments) who define research strategy and make decisions about the allocation of restricted research and development resources. MGH created the study and led data collection, analysis, and reporting. RJB supported data collection, analysis, and reporting. JB, RA, JAGS, and M-LN provided contributions to methodology and expert comment and overviews on global health, research investment, and health financing. MGH wrote the first draft. 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Much of the data awarded from 2013 onwards was sourced by accessing the Dimensions database, owned by UberResearch (London, UK). We also thank Joseph Fitchett, for his previous help and support in data collection and analysis and for assisting with secondary checks on included and excluded awards, and Pat Oxford, who provided support for developing the figures and images. JAGS is funded by a fellowship from the Wellcome Trust (214320). The study received funding from the Bill & Melinda Gates Foundation (OPP1127615).