KNOWLEDGE PORTAL
on innovation and access to medicines
BIOSECURITY RESEARCH AND DEVELOPMENT (R&D)
V1.0 researched and written by Temmy Sunyoto, reviewed by Marcela Vieira and Suerie Moon, copyedited by Anna Bezruki. Last updated November 2020.
INTRODUCTION
This work was undertaken to synthesize existing evidence on biomedical research and development (R&D) conducted by the military sector and/or relating to health security. The military is a known actor in technological or defence R&D, but its role in the (global) health R&D arena is not widely understood. The actors in biosecurity R&D have expanded beyond military agencies and evolved along with paradigms of health security.
This synthesis starts with a historical overview of military R&D, then turns to other health actors as they became increasingly involved in biosecurity R&D in recent years. The terms “biosecurity” and “biodefense” are often used for different purposes in different contexts but generally refer to “measures or protection against biological threats”.
We use the term “biosecurity R&D” in this paper to refer to the development of medical products and strategies to address biological threats to security. The products are often referred to as “medical countermeasures (MCM)”, and include drugs, vaccines, and devices to diagnose, treat, prevent, or mitigate potential health effects of exposure to chemical, biological, radiological, and nuclear (CBRN) agents and emerging infectious diseases, such as pandemic influenza.[1] Biosecurity R&D aims to prepare for public health emergencies that impact national security, and are typically considered “mission-driven”, such as the Manhattan Project or the quest for penicillin.
The literature on biosecurity R&D is considerable*, yet fragmented and dispersed. It includes both military and non-military entities as actors and focuses broadly on two areas: intentional use of CBRN agents to harm health, i.e., bioterrorism (CBRN) and unintentional spread of infectious diseases or pathogens of pandemic potential. Our literature search was limited to the English language. The literature we found focused predominantly on the United States (U.S.), which, therefore, is also the focus of this paper, unless stated otherwise.
SEARCH TERMS
Search was conducted using a combination of search mechanisms, mainly in English, with no specific time period of publication. Terms used include “military research”, “biodefense”, “biosecurity”, “bioterrorism”, “outbreaks”, “research and development”, “military medicine”, “health technologies”, “medical countermeasures”, and “emerging infectious diseases”.
SUMMARY OF THE CONTENTS
The synthesis of the literature is organized into the following topics:
SYNTHESIS OF THE LITERATURE
1. THE HISTORICAL CONTEXT OF BIOSECURITY R&D
Historically, biosecurity R&D is deeply intertwined with the military. Biomedical military research has often been claimed to be the engine of progress in medicine and surgery (Rasmussen, Reilly, and Baer 2014). Many critical medical milestones originated from the military experience, notably the triage system, wound dressing/management, antibiotic therapy, and various vaccines (Licina 2012). Military R&D typically falls under the mandate of “force health protection”, while any population health benefit is considered ancillary (Grabenstein et al. 2006).
Historically, the military has had a long-standing and well-established connection with infectious disease research, ranging from malaria to hepatitis, dengue to leishmaniasis. Disease-related morbidity, mortality, and disability that have had devastating consequences on armed troops are well documented, including the 1918 influenza pandemic which accounted for half of U.S. military casualties in Europe (Pages et al. 2010; Smallman-Raynor and Cliff 2004). Until World War II, the majority of deaths in military units engaged in combat were due to infectious diseases rather than direct combat injuries. Efforts to address these diseases gave rise to the discipline of “tropical medicine”, literally understood as “diseases of the warm climates” (Mostofi 1968; Yoeli 1972; Quail 2015; Beaumier et al. 2013). Medical army officers’ reports from stations worldwide represent some of the first epidemiological documentation of various illnesses (Mushtaq 2009). Expansion of colonial powers and empires between the 19th and 20th centuries brought about various scientific and medical breakthroughs, advancing tropical disease knowledge from basic pathogenesis and transmission to possible control measures (Hospenthal 2005). “Inoculation”, the basis of the vaccination concept, was first enacted in U.S. soldiers to prevent smallpox in 1777. In 1900, U.S. military personnel in Cuba identified a particular mosquito species as the vector transmitting yellow fever. The military also demonstrated the potential health benefits of large-scale malaria prevention campaigns, such as insecticide-treated nets and repellent (Kitchen and Vaughn 2007; Kitchen, Lawrence, and Coleman 2009). Military research stations abroad have enabled the establishment of overseas laboratory networks, which have provided an opportunity for the military to develop relations with communities in endemic countries and facilitate research collaborations (Gibbons et al. 2013).
The military contribution to the development of health tools spans across diagnostics, therapeutics, vaccines, and vector control. Vaccines are particularly attractive to the military as they can be administered pre-deployment and can have the indirect benefit of “herd immunity” (Grabenstein et al. 2006). Preventive measures are largely prioritized in many military operations as they offer advantages logistically and compliance-wise (Aronson, Sanders, and Moran 2006; Murray et al. 2007; Michel et al. 2014). At odds with the curative focus of the medical community at that time, the military research agenda was geared towards a more collective or public health approach (i.e., public health engineering, occupational health, and overall preventive interventions). Training in public health and tropical medicine were initially offered by military schools before slowly expanding to public and private universities in the mid-20th century. The contributions of U.S. military research were compiled in a 2005 supplement of the Military Medicine journal, covering: infectious diseases overall (Hospenthal 2005), vaccines (Artenstein et al. 2005), malaria (Ockenhouse et al. 2005), parasitic diseases (Crum et al. 2005), diarrhoeal diseases (Lim et al. 2005), bacterial zoonosis (Christopher et al. 2005), rickettsial diseases (Bavaro et al. 2005), sexually transmitted diseases (Rasnake et al. 2005), respiratory infections (Ottolini and Burnett 2005), hepatitis (Dooley 2005), viral hemorrhagic fever (Thomas, Lawler, and Endy 2005), and viral encephalitis (Charles H. Hoke 2005).
Table 1 below summarizes the numerous contributions of the U.S. military to health technology development, focusing on human immunization (as a key preventive method) from the 18th century to the present day.
Table 1 - Selective contributions of US military research to vaccination R&D (from the 18th century to November 2020)
a. This column refers to the time/decades/approximate year(s) considered as the start of military involvement and /or peak or R&D activities.
While the military was the primary actor engaged in biosecurity R&D for many years, as the nature, extent, and understanding of threats to health security evolved, the ecosystem expanded to include a broader range of actors. This evolution synchronously influenced the direction of military research. For example, the emergence of the Human Immunodeficiency Virus (HIV) and the ensuing AIDS pandemic was one such event. In the early 2000s, US intelligence agencies and, subsequently, the United Nations Security Council declared HIV/AIDS a national security threat and warned of instability due to the pandemic (United States. National Intelligence Council 2000; Feldbaum, Lee, and Patel 2006). According to Feldbaum et al. (2006), HIV necessitated public health investment from all sectors, including defence. The military, though it had been active in HIV prevention programs since the 1980s, subsequently expanded its dedicated research program for HIV/AIDS, including efforts to develop HIV vaccines.
Another turning point in the evolution of the biosecurity R&D system was the terrorist attack against the US on September 11, 2001 and the subsequent mailing of anthrax spores to US politicians the same year. An increased sense of vulnerability to terrorism in general, and to possible intentional dissemination of potentially fatal pathogens in particular, led to a surge in funding for infectious disease research (IoM 2002). In their review of the history of biological warfare and bioterrorism, Barras and Greub (2014) found that both were rare, but that incidents that did occur were well documented and often put forward as justification for resource allocation (Barras and Greub 2014).[1] The Severe Acute Respiratory Syndrome (SARS) outbreak in 2003 further highlighted the devastating consequences of epidemics in an increasingly globalized world and the lack of tools to prevent, detect, and respond to novel pathogens. Military research was considered an asset, a stepping stone, and a useful example for biosecurity R&D[2] more broadly, especially against emerging diseases as biological threats (Ho, Hwang, and Lee 2014).
2. ACTORS AND STAKEHOLDERS IN BIOSECURITY R&D
2.1. US actors and structure for biosecurity R&D
Moss and Michaud’s (2013) comprehensive report on the role of the US Department of Defense (DOD) in global health and infectious disease includes analysis of its sizeable medical R&D portfolio across various entities (Moss, K and Michaud 2013). The Army is designated to lead infectious diseases research within DOD with joint activity coordinated by the Military Infectious Diseases Research Program. Early-stage research is conducted mainly at the Walter Reed Army Institute of Research (WRAIR), the Naval Medical Research Center (NMRC), and the US Army Medical Research Institute of Infectious Diseases (USAMRIID). WRAIR and NMRC also conduct research overseas through divisions in Kenya, Thailand, Cambodia, Egypt, Ghana, Peru, and Singapore.[1] These research centres and their field sites focus on “prevention, diagnosis, and treatment of naturally occurring disease causing microorganisms” and allow DOD staff and partners (including academics, WHO, host-country scientists) to conduct in-country research (Gibbons et al. 2013). The Infectious Disease Clinical Research Program (IDCRP) organizes trials in military hospital networks and collaborates with civilian researchers.
Non-health-specific defence R&D is conducted by the DOD's Defense Threat Reduction Agency (DTRA) and the Defense Advanced Research Projects Agency (DARPA). DARPA was established in 1958 and tasked “to make pivotal investments in breakthrough technologies for national security” (DARPA 2015). Its success in developing pivotal technologies, including the internet, navigation, space, and stealth technologies, are detailed in its 60th Anniversary Report (DOD 2018). The Biological Technological Office oversees DARPA's projects in the biomedical field (Mervis 2016). In 2017, it launched the Pandemic Prevention Platform (P3) program with the goal to create new medicines for emerging threats within 60 days, as a temporary ‘firebreak’; this work has now been extended to the COVID19 pandemic.[2]
Emerging diseases are also the target of the US Public Health Emergency Medical Countermeasures Enterprise (PHEMCE), an initiative launched in 2006 to coordinate efforts among multiple agencies developing and acquiring countermeasures. The partners include DOD, Department of Veterans Affairs (VA), Department of Homeland Security (DHS), and the Department of Agriculture (DA), led by the Department of Human and Health Services (HHS). Agencies including the Centers for Disease Prevention and Control (CDC), Food and Drug Administration (FDA), and National Institutes of Health (NIH) are also involved. The Biomedical Advanced Research and Development Authority (BARDA) was also created in 2006, following recommendations from a 2004 report on the need to have a dedicated agency for “end-to-end development of countermeasures” (National Research Council 2004). The DOD is responsible for addressing military threats, while BARDA, as a part of HHS, focuses on threats to the civilian population. These agencies also interact with civilian researchers and industry (see Figure 1). BARDA was designed to provide an integrated, systematic approach to the development and purchase of countermeasures for public health medical emergencies (BARDA 2019). In a 2017 review, BARDA was reported to have supported ~80 product candidates for multiple CBRN threat agents, procured and stockpiled 21 of these, with 6 products having received FDA approval/licensure for a CBRN-based indication (Larsen and Disbrow 2017) (see Table 4 further below for a summary of BARDA products to date).
Figure 1 - Military and Civilian Role in the U.S. Biosecurity R&D Process
Legend: ASPR: Assistant Secretary for Preparedness and Response; BARDA: Biomedical Advanced Research Development Authority; CDC: Centers for Disease Control and Prevention; CBDP: Chemical and Biological Defense Program; CONOPS: Concept of Operations; DARPA: Defense Advanced Research Projects Agency; DHS: US Department of Homeland Security; DOD: Department of Defense; JPEO-CBD: Joint Program Executive Office for Chemical/Biological Defense; JRO: Joint Research Office; JSTO: Joint Science and Technology Office; NIAID: National Institute of Allergy and Infectious Diseases; NIH: National Institutes of Health; OPEO: Office of Preparedness and Emergency Operations; PHEMCE: Public Health Emergency Medical Countermeasures Enterprise; TMT: Transformational Medical Technology; TPP: Target Product Profile.
Source: National Research Council. 2011. Protecting the Frontline in Biodefense Research: The Special Immunizations Program. Washington, DC: The National Academies Press. https://doi.org/10.17226/13112.
2.2. Biosecurity R&D outside the U.S.
As noted in the introduction, we found limited literature available in English on biosecurity R&D conducted outside of the US. This section offers a non-exhaustive synthesis of the literature we found regarding other countries.
Many countries with a colonial history have played similar roles to the US in investing in infectious disease research (see Section 1 above). As a part of the French Military Medical Service, the Military Biomedical Research Institute conducts research, often in partnership with civilian institutions, such as the Institut Pasteur network. In contrast, clinical research is usually undertaken in-house, i.e., in military hospitals (Binder 1999). There is a long history of British military being involved with research into infectious and tropical diseases since the 16th century; this fell under the umbrella of the Defence Medical Services for many years. Defense R&D in the UK is increasingly dependent on civilian agencies for its clinical, teaching, and research activities. Since the 2000s, the majority of defense funding for microbiology and infectious disease research has been given to civilian institutions (Bailey 2013; Herron and Dunbar 2018). Many countries maintain biomedical research entities that have historical ties to, or originated from, the military (Grant 1966). Examples include the Australian Army Malaria Institute, the Germany Institute of Virology in Marburg, and Russia's S.M. Kirov Military Medical Academy (Shanks et al. 2016). The life science branch of India's Defense Research and Development Organisation (DRDO), an umbrella organization for 51 military laboratories, focuses on the well-being of troops and technological innovation (Krishan, Kaur, and Sharma 2017).
For China, the history of military medicine spans centuries, and the military maintains a role in health services through the People's Liberation Army (PLA) (Fu 2014). Almost all its biosecurity-related research is government-funded. Huang (2011) reviewed the history of China’s biodefense efforts since the set-up of the Military Medicine Institute in each military region (Huang 2011). Recent reforms in military research infrastructure resulted in an extensive network of 125 military hospitals and 15 research institutes under the umbrella of Academy of Military Medical Sciences (AMMS). Until the mid-1980s, the AMMS was devoted to research on biodefense against ‘wartime special weapons’ (i.e., atomic, biological, and chemical weapons). The Chinese military committed major resources in the 1990s to developing drugs for vector-borne diseases, including antimalarials such as benflumentol (lumefantrine), naphthoquine phosphate, and artemisinin (Chang 2016). The latter was a combination of efforts from the PLA’s Research Institute and the China Academy of Traditional Chinese Medicine, in a military project called Project 523, an example of ‘mission-oriented’ R&D (Hsu 2006; Miller and Su 2011), which was later recognized with the award to Dr. Tu Youyou of part of the Nobel Prize in Medicine in 2015.[1] According to Huang (2011), there was also increased attention to health security in China following the 2001 terrorist events in the US,[2] although there was no significant shift in the research agenda insofar as specific disease agents were concerned (Huang 2011). China's Ministry of Health appears to handle only a small set of bioterrorism agents/diseases compared to the US. Liu et al. (2014) reviewed China’s engagement in global health (including health security) over the years, and concluded that “China aspires to be a powerhouse in the discovery and production of new drugs and vaccines in global health,” but no further details were offered (Liu et al. 2014).
3. SCOPE AND PRIORITIZATION OF BIOSECURITY R&D
Military research addresses many infectious diseases. The priorities have been those that cause outbreaks and threaten military personnel: (1) conditions that spread quickly in densely populated areas (respiratory and dysenteric diseases); (2) vector-borne diseases (disease carried by mosquitoes and other insects); (3) sexually transmitted infections (hepatitis, HIV, and gonorrhoea); and (4) diseases associated with biological warfare. Military research has built on its historical legacy and evolved with newer threats or “possible unknown biological disruption,” currently specified in a priority list of pathogens[3] (Russell and Gronvall 2012). In the US, such a list is established by DOD and partners, and the categorization is reviewed regularly and published by the CDC (see Table 2 below). The US CDC list is the government's main public estimate of current biological threats and is expected to change over time.
The process to determine research priorities is complex, subject to budget and/or capacities, and may vary over time (Green et al. 2019). The level of R&D priority accorded to any particular target generally corresponds with the level of (perceived) threat, but is also influenced by various factors, such as a disease’s geographical distribution, availability of control tools, transmission methods, and the historical impact (Michaud, Moss, and Kates 2012). In the US, although the military (DOD-led) and civilian (HHS-led) R&D efforts have somewhat different missions and priorities, the agencies have also recognized a shared interest in advancing the countermeasures pipeline. They have attempted to coordinate and integrate their needs better, in the form of an Integrated Portfolio for CBRN medical countermeasures (National Research Council 2011). A 2014 evaluation recommended that DOD improve the interagency process for setting priorities (U. S. Government Accountability Office 2014).
Table 2 - List of priority pathogens, as identified by the US Centers for Disease Control (as of November 2020)
Source: CDC and NIAID; Available from https://emergency.cdc.gov/agent/agentlist-category.asp and https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens. Last accessed on 01 November 2020.
In terms of health technology type, preventive measures predominate. Initially targeting specific diseases, wartime programs expanded the scope of the military's work in vaccines, which benefited both the military and civilians. One oft-cited example is the organizational purpose and efficiency of the commission organized by the US Army in 1941 to develop the first influenza vaccine, licensed by the FDA in two years (Hoyt 2006).[1] The partnership between military and civilian actors, including the private sector and industrial partners, was considered vital and extended until the Cold War and beyond (Sarewitz 2011). Another example is the penicillin project, in which discoveries in military labs were further developed by pharmaceutical companies in close cooperation, and with transparent, regular scientific exchanges (Quinn 2013). The “generational” process of vaccine development (i.e., continual improvement, with newer version(s) that are safer, more effective, or more user-friendly) was performed by the industry, which further developed them for routine immunization.[2] Hoyt (2006) argued that the collaboration between the military and industry partners accelerated vaccine innovation through the middle of the 20th century, with sustained cooperation even after the urgency and structure of wartime programs were dissolved. Maslow (2017) further attributed the strength of the military-industrial partnership to legal, economic, and political changes in the U.S during the 1970s -80s, such as the FDA’s increasing authority in regulating vaccines and the emergence of biotechnology firms. Though the US DOD continues to pursue vaccines as a cost-effective solution (to prevent infectious diseases and protect combat-ready personnel), the industry is needed to manufacture them. However, vaccines that are marketed commercially have proven to be more attractive for the pharmaceutical industry, while some countermeasure vaccine candidates have languished in government labs (including the military) (Dembek et al. 2017; Trull, du Laney, and Dibner 2007).
Other than emerging infectious diseases, the US military has also prioritized malaria and HIV/AIDS, as evidenced by their continued vaccine efforts. Malaria poses a continuing threat to military operations in the regions of the world where it is endemic. Current malaria countermeasures include drug prophylaxis and treatment, vector control, and personal protection (topical repellents, clothing, and bed nets) – yet no vaccine has been licensed globally for adults. DOD institutions have contributed to the development of many widely-used antimalarial drugs: chloroquine, primaquine, mefloquine, doxycycline, atovaquone/proguanil, and, most recently, tafenoquine (Ockenhouse et al. 2005; Zottig et al. 2020; Kitchen, Lawrence, and Coleman 2009; Kitchen, Vaughn, and Skillman 2006). For HIV/AIDS, the DOD laboratories play a crucial role, alongside NIAID, in pursuing vaccine R&D since 1985 (Table 1). HIV remains a significant threat to US service members deployed overseas. Another increasingly important focus is antimicrobial resistance (AMR), which has come under increasing global attention.[3]
As for diseases with importance beyond military concern, biosecurity R&D has gradually moved towards health technologies that can not only be used for emergencies but may also be beneficial in general medical care (e.g., burn care, radiation effects suffered by cancer patients, seizures, etc.) (Warfield and Aman 2016). As the occurrence of biological events is unpredictable, the idea of broad-spectrum technologies (multiplex or multi-use platforms; pathogen agnostic) that can be easily adjusted towards various pathogens and scaled up started to be more actively pursued as a goal in biosecurity research (DeFrancesco 2004; Casadevall et al. 2008).
4. FUNDING, INCENTIVES AND LANDSCAPE OF BIOSECURITY R&D
4.1. Biosecurity R&D Funding at the US federal level
Internationally, global spending on R&D has been on the rise[4] (with the impact of Covid-19 still to be fully grasped). However, it is not straightforward to estimate investment in biosecurity R&D. This section synthesizes funding figures from various sources in the literature.
The US National Science Foundation reports on the federal R&D budget each year by department and purpose (summarized below in Figure 2).
Figure 2 - Breakdown of US federal research and development budget, 2015*
*Total of R&D budget for 2015 amounted to 131.4 billion USD; Details may not add to total because of rounding.
Legend: DOC: Department of Commerce. DOD: Department of Defense; DOE: Department of Energy; HHS: Department of Health and Human Services; NASA: National Aeronautics and Space Administration; NSF: National Science Foundation; USDA: Department of Agriculture.
Source(s): National Science Foundation, National Center for Science and Engineering Statistics, Survey of Federal Funds for Research and Development. Science and Engineering Indicators 2018. Available from: https://www.nsf.gov/statistics/2018/nsb20181/figures
According to a 2019 report from the American Academy for the Advancement of Science, the federal R&D budget surged steeply after 2001, and despite a brief decline in 2010-2013 due to the financial crisis, has increased gradually again. Defence has long been a priority, accounting for almost half of federal R&D support, reaching $51 billion in 2017 (“Report - S&E Indicators 2018 | NSF - National Science Foundation” n.d.). Basic and applied research is generally funded by nondefense agencies such as NIH or NSF. Although the DOD R&D budget focuses on the later stages of research (development/advanced manufacturing, facilities, procurement), military labs and DARPA also conduct more upstream research.
Disaggregated, specific funding data on biosecurity R&D is difficult to find, as it is funded through different programs in various agencies. Furthermore, there is no formal US government definition of what counts as biosecurity R&D, and activities may fall under broader categories such as “defense,” “global health,” “biosecurity,” or “EID”. Table 3 provides a summary of funding data relevant for biosecurity R&D. As highlighted by the various figures and reporting methodologies in Table 3, it is difficult to find a single number that clearly represents total US funding for biosecurity R&D.[1]
Table 3 - Selected US funding estimates relating to biosecurity R&D
Legend: BARDA: Biomedical Advanced Research Development Authority; CDC: Centers for Disease Control and Prevention; DOD: Department of Defense; FDA: Food and Drugs Administration; KFF: Kaiser Family Foundation; MCM: Medical Countermeasures; NIH: National Institutes of Health; PHEMCE: Public Health Emergency Medical Countermeasures Enterprise; SNS: Strategic National Stockpile; TMT-DTRA: Transformational Medical Technologies – Defense Threat Reduction Agency; UPMC: University of Pittsburgh Medical Center; US: United States of America.
a. For the scope of EID in Policy Cures Research, see https://gfinderdata.policycuresresearch.org/pages/data-visualisations/usa.
4.2. Push and pull incentives for biosecurity R&D in the US
In the last 20 years, the lack of licensed vaccines, diagnostics or therapeutics for many pathogens considered a priority threat has spurred the US government to mobilize various push and pull incentives to address the issue (National Research Council 2004). There is limited interest from the private sector to develop biodefense products, as typically there is high risk, and limited commercial markets until a large-scale outbreak actually occurs (Smith, Inglesby, and O’Toole 2003). Several of these pull and push incentives are briefly described here.
Project Bioshield was enacted in 2004 to ensure late-stage development, manufacturing, procurement, and stockpiling of strategic assets for public health emergencies. Managed by DOD, this program basically augments market incentives for companies by committing to advanced purchases, accompanied by tax incentives, intellectual property protection, and liability limits (Nolan et al. 2010; Trull, du Laney, and Dibner 2007). Matheny et al. (2007) reviewed several ‘push’ and ‘pull’ mechanisms to incentivize biosecurity product development, which includes government technology transfer, industrial collaboration, grants, prizes (e.g., DARPA Challenge), exclusivity and procurement contracts – each with its strength and weakness (Matheny et al. 2007). The system has developed many products (see Table 4 below) but has not always been successful; a 2010 GAO report found that the firm VaxGen failed to deliver on an anthrax vaccine contract in 2006, while the FDA-licensed anthrax vaccine expired in the stockpile (GAO 2010).
Table 4 - Products developed by US BARDA (as of October 2020)
Sources: Data collated from BARDA https://www.phe.gov/about/barda/Pages/default.aspx and https://www.medicalcountermeasures.gov/barda/.
Last accessed on 30 October 2020.
Regulatory measures such as the Emergency Use Authorization option and the Animal Efficacy Rule, were also established to accelerate biosecurity product development. The latter allows the FDA to approve products for “serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances” based on animal models alone.[1] (Aebersold 2012; Gronvall et al. 2007). Another regulatory incentive was the addition of the ‘medical countermeasures’ category in 2016 to the Priority Review Voucher (PRV) mechanism. The PRV was created in 2007 to facilitate the development of drugs with insufficient commercial markets, typically rare paediatric and neglected tropical diseases.[2] The PRV grants the sponsor a voucher that can be used for accelerated review of any subsequent new drug or biologic in development or be sold to the highest bidder.
The 21st Century Cures Act of 2016 included further efforts to accelerate biosecurity R&D. For example, it authorized BARDA to partner with entities that use venture capital practices and methods (U. S. Government Accountability Office 2020). Several examples include DOD's DeVenCi, the Army's OnPoint, Red Planet, or the CIA's In-Q-Tel[3] – all of which are approaches to mobilize private funding for the early discovery stage (Institute of Medicine (US) Forum on Drug Discovery 2010). For countermeasures development, the government would invest in technology development by a company, and the return on investment is considered to be products. In 2018, BARDA launched the Division of Research, Innovation, and Ventures, for “transforming health security by connecting federal government, scientists and venture capital investors” (“DRIVe” n.d.). Since 2013, BARDA has also been given greater flexibility in providing grants, for example, through the establishment of partnerships through ‘Other Transactions Authority’ or Other Transaction Agreements (OTAs). OTAs allow BARDA to collaborate with large pharmaceutical companies or other consortia to address market failure in certain fields, for example in antibiotics development (Houchens and Larsen 2017). The main difference between OTAs and traditional contracts with the federal government is that they are generally exempt from federal procurement laws and regulations. The terms of all provisions of an OTA are considered negotiable including on intellectual property rights, therefore allowing the pharmaceutical companies to continue to pursue profits as usual (Schwartz and Peters 2019). OTAs are defined as transactions other than procurement contracts, grants, and cooperative agreement, and are regarded as being exempt from laws that protect taxpayers and that give the government rights in publicly-funded data and IP (KEI 2020).
Matheny et al. (2008) estimated costs and projections for the US biosecurity pipeline against selected HHS targets (e.g., anthrax vaccine, anthrax antitoxin, filovirus vaccine, filovirus antiviral, Junin virus antiviral, smallpox antiviral, broad-spectrum antibiotic against Gram-positives and Gram-negatives bacteria). Their analysis included only drugs and vaccines, and used various data sources to identify candidates (e.g., pharmaceutical and biotech companies’ press releases and quarterly and/or annual reports, news reports, US government agency reports and databases, and a 2006 biodefense market survey).[4] On the basis of historical pharmaceutical success/failure rates, the probability of at least one approved product within the existing pipeline varied: 85% for an anthrax vaccine, 72% for an anthrax antitoxin, and 12% for an antibiotic (Matheny, Mair, and Smith 2008). The authors concluded that to yield at least a 90% probability of one approved product for each category, the pipeline and BARDA funding would need to both double.
4.3. Landscape of biosecurity R&D
Russell and Gronvall (2012) reviewed US biosecurity R&D since 2001. The paper noted some progress, such as the simplification of the acquisition process and “smallpox readiness” (Russell and Gronvall 2012). However, various reviews have identified many issues, notably in leadership, coordination, and challenges in working across “the complex interagency, intergovernmental, and intersectoral biodefense enterprise” (U. S. Government Accountability Office 2014; IoM 2002). In 2011, the GAO found a lack of a broad, integrated national strategy that encompassed all stakeholders with biosecurity responsibilities; a national biodefense strategy was subsequently launched in 2018 (US Government Accountability Office 2011).
Trull et al. (2007) documented the global biosecurity market in 2006 by assessing commercial drug pipeline databases, government publication and websites, and pharmaceutical industry news to determine the stages of the products in development and comparing them against the CDC list of priority pathogens. They found 152 prophylactic vaccines, with 102 in preclinical development, 35 in Phase 1, 12 in Phase 2 and only three in Phase 3.[5] As for vaccines, the therapeutic pipeline was dominated by products in preclinical development (129), with only 16 in clinical trials. The paper also reported that 189 entities were involved in a biosecurity program, with 95 groups spread over 19 countries that were developing vaccines, and 94 groups in 14 different countries developing therapeutics. Sixty-two percent of these groups were located in the US – partially due to the large number of pharmaceutical and biotech companies there, but also due to the availability of sources to identify and confirm their involvement in biosecurity product development. The authors also identified several challenges of biosecurity product development, including having to address multiple infections or serotypes from the same agent, rapidly changing public health priorities in infectious diseases, and necessary product attributes, such as the possibility of high-volume administration (Trull, du Laney, and Dibner 2007).
Milne et al. (2017) reported the results from the Tufts Center for the Study of Drug Development (CSDD) review of global medical countermeasure landscape from 2016 (C. Milne, Smith, and Chakravarthy 2017). There has been an expansion in terms of the number of products in the pipeline, as compared to 2008 (263 versus 592 in 2016) (see Figure 3). There has been rapid growth in the pipeline for influenza, Ebola (which caused major outbreaks in 2014 and 2018), and Zika (which caused a major outbreak in 2015-2016), but not for ‘biodefense only’ products, such as those for smallpox or anthrax. More than half of all MCMs in development (332 products, 56%) are for just five indications, while the remaining 57 indications have a total of only 289 products, or 4.5 candidates on average per indication. The category of products that applied mainly to bioterrorism tends to be purchased in bulk by governments and is limited in terms of market growth after reaching a plateau of volume needed for stockpiles. The authors argued that the primary market drivers for the private sector thus would be the availability of government funding and the continued threat posed by various pathogens as reflected in the threats list.
The number of companies that are active in developing countermeasures also reportedly increased: from 133 in 2008 to 303 in 2016. The top five countries where these companies (generally small and medium enterprises (SMEs)) are based are the US (159 companies), China (33), UK (12), Canada (10), and Switzerland (10). The role of SMEs appears to be important: SMEs account for 86% of the countermeasures pipeline, although the majority are in early stage development.[6] Only ~3% of products in development by the 25 biggest pharmaceutical companies are countermeasures, although their role increases in later-stage development (C. Milne, Smith, and Chakravarthy 2017; C.-P. Milne 2019). According to the same authors in a blog post on countermeasure development in Asia, China is the world’s second most active country in terms of its countermeasure pipeline (with 52 products in development or 49% of the Asian pipeline) followed by South Korea, India, Japan, Malaysia, Thailand, and Singapore. In terms of priority, the top indications in the pipeline are rabies (23%), typhoid (9%), hepatitis A (9%), and Japanese encephalitis (7%). Notably, these indications do not necessarily overlap with the US CDC priority-pathogens list, underscoring that threats considered a priority in one region of the world may differ from those in another. When it comes to specific products, Li et al. (2020) described China’s R&D for Ebola: total funding of up to CNY 44.05 million (USD 6.27 million), predominantly in the basic research phase (87.8%), resulting in the Ad5-EBOV vaccine and six Ebola-related products approved by the National Medical Products Administration of China (Li, Chen, and Huang 2020).
Figure 3 - The pipeline for medical countermeasures in 2016
a. Number of products in development for the most common medical countermeasure-related indications. b | Trends in the pipelines for selected medical countermeasures, illustrating the different drivers of product development.
Source: Milne, C., Smith, Z. & Chakravarthy, R. Landscape for medical countermeasure development. Nat Rev Drug Discov 16, 448 (2017). https://doi.org/10.1038/nrd.2017.80 (Figure used with permission)
The G-FINDER project tracks annual investment in R&D for new products and technologies, including for EID, in which many of the diseases overlaps with biosecurity targets (Policy Cures Research, 2020). [1] Global funding for EID R&D is very narrowly focused on recent large-scale outbreaks, and the US government plays a dominant role in both product-specific and early-stage research. During the period of 2014-2018, there was an increase in EID basic research, which reached USD 886 million in 2018. The identified drivers were the Ebola and Zika epidemics, the establishment of the Coalition for Epidemic Preparedness Innovations (CEPI), and growing investment in ‘Disease X’ as an R&D priority. Overall EID funding in 2014-2018 was focused on vaccine R&D (51%), followed by basic research (17%), biologics (9.4%), and drugs (6.7%). The dominance of vaccine funding peaked in 2015, at the height of the West African Ebola epidemic, at nearly 70% of the global total, though this has since declined, reflecting the reactive nature of EID funding to date.
5. CONCLUDING REMARKS
This paper has offered a synthesis of the English-language literature on biosecurity R&D, and – reflecting the literature – has focused heavily on the US system. The overall approach for biosecurity R&D in the US can be summarized as: identifying current and future threats, setting priorities for countermeasure development, investing public funds directly in R&D by public and private actors, and providing incentives for private investment and R&D activity. The purpose, capacity, and financing of R&D for biosecurity influences the way R&D efforts are organized. Biosecurity R&D was built on a historical legacy of military R&D, with sustained investment from the government budget. The driver of continued military investment in R&D is civic duty and a mandate to protect national security. Private sector involvement in biosecurity R&D is heavily shaped by public funding, and legal, regulatory, technological, and financial incentives. Overall, increased awareness of the threat of emerging and re-emerging infectious disease outbreaks, seems to determine which countermeasures are a priority and how quickly they progress through the pipeline. The Covid-19 pandemic is likely to have profound impacts on national and global approaches to biosecurity R&D; this paper has offered a picture of the US pre-Covid-19 countermeasure R&D system, experiences from which are likely to shape policy debates in the years to come.
RESEARCH LIMITATIONS AND GAPS
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Reviews of existing literature in languages other than English and covering other countries
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Insufficient studies on funding for biosecurity R&D
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Insufficient studies on outcomes of biosecurity R&D, and comparisons with time, success rates, and costs for other health technologies
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Insufficient empirical studies on the model of biosecurity R&D compared to other areas
NOTES
[1] The term medical countermeasures also include technologies that might assist the development or use of medical countermeasures. CBRN agents can be natural, accidental, or intentional in origin.
[2] For extensive discussions on bioweapons, including the grey areas of “offensive”’ or “defensive” biodefense research see: Studies of Military R&D and Weapons Development: Offensive/Defense Distinctions in BW Related Research: https://fas.org/man/eprint/leitenberg/off-def.pdf
[3] "Bioterrorism” remains distinct from "naturally occurring disease" in intent and application, both are seen to require dedicated R&D. Biosecurity R&D programs’ goals are explicitly devoted to “detect, prevent, and treat CBRN threats”, with the "biological" portfolio covering both weaponized pathogens and disease outbreaks caused by "emerging and re-emerging" infectious diseases.
[4] The US Army Medical Research Unit (USAMRU) in Kenya, and the Armed Forces Research Institute of Medical Sciences (AFRIMS) in Thailand are important for WRAIR’s research on many infectious diseases. The Naval Medical Research Centre also performs research and conducts surveillance through its Naval Health Research Center (NHRC). Its units (NAMRUs) also allow in-country research on a number of infectious diseases.
[5] In the COVID19 pandemic, DARPA P3 is funding four projects, including one in search of antibodies for treatment: https://www.c4isrnet.com/coronavirus/2020/03/17/darpa-backed-pandemic-readiness-could-yield-results-by-july/
[6] The central government set up a panel of more than 500 medical military and civilian experts to develop new antimalarial treatments for soldiers. This was classified as a top-secret state mission named Project 523, after the date it was established 23 May 1967. Source: https://www.who.int/bulletin/volumes/87/10/09-051009/en/
[7] Also in Huang (2011), search using “bioterror” (shengwu kongbu) as a keyword search term for articles from the “China Academic Journals Full-text Database,” which covers almost all academic journals published in China (in Chinese), found that prior to 2001 bioterrorism was rarely discussed, and post-2001 there was a significant increase in the number of publications. Of the articles that include “bioterror” in their key words since 1979, nearly 99% were published after 2001.
[8] These would include several diseases that have re-emerged and caused global concern in recent years, such as Zika, SARS, Middle East Respiratory Syndrome (MERS) viruses, and Ebola. Following lessons from Ebola outbreaks (both 2014 and 2018), the WHO has published an R&D BluePrint. The Blueprint 2019 has listed the following as priority pathogens: Crimean-Congo hemorrhagic fever (CCHF), Ebola virus disease and Marburg virus disease, Lassa fever, MERS, SARS, Nipah and hantavirus diseases, Rift Valley fever (RVF), Zika and Disease X.
[9] All health technologies designated for US troops must be approved by the FDA.
[10] This has occurred for example with the Haemophilus influenzae type b (Hib), pertussis, pneumococcal, and hepatitis B vaccines.
[11] CARB-X was launched in 2016 as the world’s largest public-private partnership dedicated to accelerating antibacterial research to tackle the global rising threat of drug-resistant bacteria, a collaboration between BARDA, NIAID/NIH and the UK Wellcome Trust.
[12] OECD Main Science and Technology Indicators, 2018. http://www.oecd.org/sti/msti.htm. Accessed 18/08/2020
[13] An annual review reporting federal funding for health security programs is conducted by Johns Hopkins University Center for Health Security, published in the journal Health Security, for federal programs focused on prevention, preparedness, and response to attacks on civilians with biological agents and accidental releases of biological material. The latest one is available at: https://www.liebertpub.com/doi/10.1089/hs.2018.0077
The definitions used: Radiological and Nuclear Security: Federal programs focused on prevention, preparedness, and consequence management of radiological and nuclear terrorism and large-scale radiological accidents; Chemical Security: Federal programs focused on prevention, preparedness, and response to large-scale acute chemical exposures of civilian populations, both intentional and accidental; Pandemic Influenza and Emerging Infectious Diseases: Federal programs focused on preparedness and response to large, naturally occurring, and potentially destabilizing epidemics; and Multiple-Hazard and General Preparedness: Federal programs focused on multiple hazards or on building infrastructure and capacity to respond to large-scale health threats.
[14] To date, only a small handful of products were approved based on the rule: J&J's Levaquin (levofloxacin) for plague and GSK's raxibacumab for inhalation anthrax in 2012, Cangene’s antitoxin for botulism in 2013, and Bayer Healthcare's Avelox (moxifloxacin) in 2015 also for plague (although the drug is also approved for other diseases.
[15] See Knowledge Portal on Innovation and Access to Medicines Research Synthesis on PRV: https://www.knowledgeportalia.org/priority-review-vouchers
[16] DeVenCi (Defense Venture Catalyst Initiative) is a DOD program to increase awareness of emerging technologies developed outside traditional DOD procurement. OnPoint and In-Q-Tel provide funding for technologies that directly benefit its target but also have applicability in the commercial sector. Both models rely on the clear demand expressed by the respective government agencies. In-Q-Tel identifies and invests in companies developing these technologies.
[17] From (Trull, du Laney, and Dibner 2007); and the previous year’s work: Trull, Laney & Dibner 2006. Biodefense Market Report: vaccines, therapeutics, and diagnostics for bioterror agents 2006 BioAbility/BioWorld Atlanta GA (June 2006) – not available in the public domain.
[18] 24 for anthrax, 19 for smallpox, 13 for plague, 14 for viral encephalitis and 28 for avian influenza. For therapeutics in development, 155 products were identified, with a similar distribution of targets (20 for smallpox, 18 for viral encephalitis, 17 for anthrax, 14 for SARS and 16 for avian influenza.
[19] See Knowledge Portal on Innovation and Access to Medicines, Research Synthesis: Role of Small and Medium-sized Enterprises, 2019, available at https://www.knowledgeportalia.org/small-and-medium-enterprises.
[20] Policy Cures Research defines EID as including the following disease groups: Ebola and Marburg, Zika, Lassa fever, Coronaviruses (Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome), Crimean-Congo Haemorrhagic Fever and Rift Valley Fever, Nipah and henipaviral diseases, Disease X and other non-disease-specific funding.
CITED PAPERS WITH ABSTRACTS
*For the purposes of this review, we have established three categories to describe the state of the literature: thin, considerable, and rich.
- Thin: There are relatively few papers and/or there are not many recent papers and/or there are clear gaps
- Considerable: There are several papers and/or there are a handful of recent papers and/or there are some clear gaps
- Rich: There is a wealth of papers on the topic and/or papers continue to be published that address this issue area and/or there are less obvious gaps
Scope: While many of these issues can touch a variety of sectors, this review focuses on medicines. The term medicines is used to cover the category of health technologies, including drugs, biologics (including vaccines), and diagnostic devices.
Disclaimer: The research syntheses aim to provide a concise, comprehensive overview of the current state of research on a specific topic. They seek to cover the main studies in the academic and grey literature, but are not systematic reviews capturing all published studies on a topic. As with any research synthesis, they also reflect the judgments of the researchers. The length and detail vary by topic. Each synthesis will undergo open peer review, and be updated periodically based on feedback received on important missing studies and/or new research. Selected topics focus on national and international-level policies, while recognizing that other determinants of access operate at sub-national level. Work is ongoing on additional topics. We welcome suggestions on the current syntheses and/or on new topics to cover.
Open Access: This research synthesis is published Open Access, and distributed in accordance with the Creative Commons Attribution Non Commercial International (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. Third party material are not included. See: https://creativecommons.org/licenses/by-nc/4.0/.
