Clinical Infectious Diseases VIEWPOINTS

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1 Clinical Infectious Diseases VIEWPOINTS Project BioShield and the Biomedical Advanced Research Development Authority: A 10-Year Progress Report on Meeting US Preparedness Objectives for Threat Agents Joseph C. Larsen and Gary L. Disbrow Division of Chemical, Biological, Radiological and Nuclear Medical Countermeasures, Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response, US Department of Health and Human Services, Washington, District of Columbia The Biomedical Advanced Research and Development Authority (BARDA) conducts the advanced research and development and procurement of vaccines, therapeutics, and diagnostics for chemical, biological, radiological, and nuclear (CBRN) threats, pandemic influenza, and emerging infectious diseases. Since its inception in 2006, BARDA has played a critical role in partnering with industry to advance candidates in development toward US Food and Drug Administration (FDA) approval and then procuring them for potential use in a public health emergency. A decade into its existence, we now reflect on how BARDA has improved the preparedness posture of the United States against CBRN threat agents. BARDA has stockpiled or is the process of stockpiling 21 products for potential use in public health emergencies. Six products have achieved FDA approval or licensure. For several threat agents, the entire repertoire of medical countermeasures that have been procured and stockpiled should serve as a substantial deterrent to their future use in an attack. Keywords. BARDA; public health emergency preparedness; bioterrorism; medical countermeasures. The attack on Americans on 11 September 2001 and the events surrounding the anthrax attacks of 2001 highlighted the need for medical countermeasures: vaccines, therapeutics, and diagnostics to protect US citizens from chemical, biological, radiological, and nuclear (CBRN) threats. At the time, however, there were very few companies developing these products due to their limited commercial returns. The Project BioShield Act of 2004 was signed into law in July of 2004 to fundamentally augment market incentives for companies pursuing the development of CBRN medical countermeasures [1]. The Act provided $5.6 billion over 10 years to develop, purchase, and stockpile medical countermeasures for use in a public health emergency, such as a CBRN terrorism event. The Pandemic All Hazards Preparedness Act of 2006 (PAHPA) established the Biomedical Advanced Research and Development Authority (BARDA), under the Assistant Secretary for Preparedness and Response, to serve as the US government s focal point for the advanced research and development and procurement of medical countermeasures for Received 27 October 2016; editorial decision 7 January 2017; accepted 27 January 2017; published online February 04, Correspondence: J. C. Larsen, Division of Chemical, Biological, Radiological and Nuclear Medical Countermeasures, Biomedical Advanced Research and Development Authority (BAR- DA), Office of the Assistant Secretary for Preparedness and Response, US Department of Health and Human Services, Washington, DC (joseph.larsen@hhs.gov). Clinical Infectious Diseases 2017;64(10): Published by Oxford University Press for the Infectious Diseases Society of America This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: /cid/cix097 CBRN threats, pandemic influenza, and emerging infectious diseases. Most recently, the Pandemic All Hazards Preparedness Reauthorization Act of 2013 (PAHPRA) continues BARDA s role and reauthorized Project BioShield funding at $2.8 billion for fiscal years and provided BARDA with $415 million in annual appropriations to support advanced research and development [2]. BARDA utilizes the provided funding to administer a combination of push and pull incentives to mobilize pharmaceutical and biotechnology companies to pursue medical countermeasure development. The push incentives provided through advanced research and development contracts lower the risk assumed by the sponsor while the pull incentives provided under Project BioShield allow for a market commitment that provides a predictable return on investment for their products. BARDA has used these incentives to build a robust pipeline of approximately 80 candidate medical countermeasures for multiple CBRN threat agents. It has also procured and stockpiled 21 of these for potential use in the event of a public health emergency. Of these, 6 products have received US Food and Drug Administration (FDA) approval/licensure for a CBRN-based indication. Since its inception in 2006, BARDA has made several key investments in the development of medical countermeasures for CBRN threats. This article provides a summary of key accomplishments under Project BioShield and describes how the level of preparedness against multiple threats has increased as a result. The products that BARDA has supported under Project 1430 CID 2017:64 (15 May) Larsen and Disbrow

2 BioShield since 2005 are described in Table 1. This article does not focus on BARDA s programs on pandemic influenza or emerging infectious diseases. Many of the candidate products discussed below have transitioned to BARDA from partners within the Public Health Emergency Medical Countermeasures Enterprise (PHEMCE), a coordinated group of US federal agencies tasked with developing and operationalizing medical countermeasures [3]. BARDA works closely with other federal agencies (eg, Department of Defense) to leverage and share stockpiled products to reduce the disposition of products. We also discuss potential future strategies and areas of interest that BARDA may support in its next iteration from 2018 to Anthrax has been a priority threat for BARDA and our PHEMCE partners to address since the 2001 attacks. BARDA s investments in anthrax preparedness through the private sector have resulted in the FDA approval of 3 immunoglobulin-based products for the treatment of inhalational anthrax [4, 5]. Two Table 1. Medical Countermeasures Supported Under Project BioShield of these products, raxibacumab and obiltoxaximab (ANTHIM), are monoclonal antibodies while Anthrasil (anthrax immune globulin intravenous [human]) is a polyclonal immunoglobulin-based product. All 3 products have pediatric dosing recommendations on the label. BARDA also obtained an additional indication for Biothrax (anthrax vaccine adsorbed), which allows for the vaccine to be used as a postexposure prophylaxis countermeasure, and licensed a large-scale manufacturing facility/process to allow for greater production of anthrax vaccine(s) to meet requirements or to ramp up manufacturing in response to an incident. Both the vaccine and antitoxin products, when combined with currently stockpiled broad-spectrum antibiotics, allow for a comprehensive and robust capability to respond to an anthrax attack. Additional efforts are focused on improving the operational feasibility of the response and lowering sustainment costs of stockpiling, deployment, and total life cycle management. Examples of this include the late-stage Product Company Threat Use Status Raxibacumab GlaxoSmithKline Anthrax Treatment of inhalational anthrax FDA approved Anthrasil (anthrax immune Emergent Biosolutions Anthrax Treatment of inhalational anthrax FDA approved globulin) ANTHIM (obiltoxaximab) Elusys Therapeutics Anthrax Treatment of inhalational anthrax FDA approved Biothrax (anthrax vaccine adsorbed) Emergent Biosolutions Anthrax Postexposure prophylaxis FDA approved Nuthrax (anthrax vaccine adsorbed with CPG 7909 adjuvant) Heptavalent botulism antitoxin (HBAT) IMVAMUNE (modified vaccine Ankara) Emergent Biosolutions Anthrax Postexposure prophylaxis Emergent Biosolutions Botulism Treatment of symptomatic botulism FDA approved Bavarian Nordic Smallpox Prevention of smallpox for use in people where replicating smallpox vaccines are contraindicated Stockpiled for emergency Tecovirimat (ST-246) SIGA Technologies Smallpox Treatment of smallpox infection Stockpiled for emergency Versed (midazolam) Meridian Medical Technologies/ Pfizer Nerve agents Treatment of nerve-agent induced seizures Neupogen (filgrastim) Amgen Radiation Treatment of the myelosuppressive Leukine (sargramostim) Sanofi Radiation Treatment of the myelosuppressive Neulasta (pegfilgrastim) Amgen Radiation Treatment of the myelosuppressive FDA approved Stockpiled for emergency FDA approved ThyroShield Fleming Radiation Thyroid blocking agent FDA approved Ca-DTPA Akorn Radiation Chelating agent FDA approved Zn-DTPA Akorn Radiation Chelating agent FDA approved Silverlon Argentum Thermal or radiation Antimicrobial wound dressing FDA approved Nexobrid Mediwound Thermal or radiation Enzymatic debridement of wounds Recell Avita Medical Americas LLC Thermal or radiation Donor graft sparing technology Stratagraft Stratatech Thermal or radiation Artificial skin substitute REDI-Dx Dxterity Biodosimetry Detect/quantify level of radiation exposure ARad MRI Global Biodosimetry Detect/quantify level of radiation exposure Abbreviations: Ca-DTPA, pentetate calcium trisodium; EUA, Emergency Use Authorization; FDA, US Food and Drug Administration; Zn-DTPA, pentetate zinc trisodium. Project BioShield and BARDA: 10-Year Progress Report CID 2017:64 (15 May) 1431

3 development and procurement of Nuthrax (anthrax vaccine adsorbed with CPG 7909 adjuvant), a next-generation anthrax vaccine intended to confer protective immunity after 2 doses vs 3 doses for the currently stockpiled Biothrax [6]. The improved onset of immunity and reduced stockpiling footprint allow for reduced quantities of vaccine as well as the antibiotics that would be part of a postexposure prophylaxis regimen. BARDA supported the late-stage development, procurement, and FDA approval of a therapy for botulism intoxication. Heptavalent botulism antitoxin (HBAT), approved by the FDA in March 2013, is the only available therapy capable of treating all 7 serotypes of botulism. HBAT was approved to treat adult and pediatric patients with symptomatic botulism following documented or suspected exposure. BARDA s support of this product has improved our ability to respond to an attack with botulinum neurotoxin. An additional benefit of this product is that it can be also dispensed and used to provide treatment in foodborne botulism outbreaks [7]. Smallpox is another major threat that BARDA has made progress in addressing. BARDA has developed, procured, and stockpiled IMVAMUNE (modified vaccinia Ankara virus), a smallpox vaccine intended for use in patients where the replicating smallpox vaccine (ACAM2000) would be contraindicated. This includes individuals who have human immunodeficiency virus (HIV) infection or atopic dermatitis. IMVAMUNE is currently available for potential use during a declared emergency, under Emergency Use Authorization (EUA) in individuals with HIV or atopic dermatitis to include all age ranges and women who are pregnant or nursing. IMVAMUNE supplements our current response capability by protecting at-risk populations in the event of smallpox exposure. Developing countermeasures for at-risk populations is a mandate of the PAHPA. BARDA will continue to work toward full licensure of this product. During a smallpox event, however, there is a strong likelihood that there would be individuals who are infected and become symptomatic. To treat these patients, an antiviral drug is required. In 2011 BARDA initiated late-stage development and procurement of tecovirimat (ST-246) for the treatment of symptomatic smallpox infection. Tecovirimat works by inhibiting viral egress and has been shown to be effective in several animal models of orthopox virus infection [8, 9]. Tecovirimat is currently stockpiled for potential use during a declared emergency under EUA. A human safety study has been completed and a new drug application submission is anticipated for the end of As a result of BARDA s investments and those of the Strategic National Stockpile, there are now sufficient stockpiles of both vaccine and antiviral drugs to effectively respond to a smallpox event. Chemical threat agents remain one of the most widely used CBRN agents. Their recent use in conflicts such as the civil war in Syria serves as a continual reminder of the feasibility of these agents to be used here domestically in an attack. One particularly deadly chemical threat class is nerve agents, which overactivate and cripple the cholinergic nervous system. People exposed to these agents can have dramatic and prolonged seizures that can result in significant and permanent neurological impairment. To address this class of threats, BARDA supports late-stage development and procurement of midazolam as an antiseizure medication to reduce the impact of nerve agents on the neurological system. Midazolam (Versed) is an FDAapproved medication and BARDA is supporting the formulation of the product into an autoinjector that would allow for rapid intramuscular injection and bioavailability of the product. This product is currently in late-stage development and is projected to be available for emergency use in Prior to the establishment of Project BioShield and BARDA, the US government possessed limited capability to respond to a radiation or nuclear event from a medical countermeasure perspective. Over the last decade several key capabilities have been established. One of the primary obstacles to providing medical treatment in an event involving radiation is triaging patients who have been exposed and are in need of treatment from those who have not been exposed. BARDA is supporting the late-stage development and procurement of biodosimetry devices that quantify the level of radiation an individual has been exposed to. The biodosimetry devices detect alterations in genetic and protein markers and can assess whether someone has been exposed to 2 gray (Gy) or more of radiation. A determination of exposure would allow for appropriate triage of people and would reserve medications for patients who actually need them. Diagnosing acute radiation syndrome is challenging because the symptoms can take days or weeks to manifest. BARDA is supporting the late-stage development and potential procurement of 2 high-throughput devices that will be established in commercial diagnostic labs. Radiation Exposure Dosage Index Diagnostic (REDI-Dx) and ARad Biodosimetry Test are both innovative molecular gene expression tests that detect a panel of genomic markers in blood that are altered after exposure to ionizing radiation. The device will better inform a response by identifying individuals who truly need further treatment. Exposure to radiation manifests by a set of symptoms and subsyndromes that involve the hematopoietic, gastrointestinal, and pulmonary systems. For the hematopoietic system, there is a destructive effect that results in profound neutropenia and thrombocytopenia. BARDA supported the procurement of immunostimulatory cytokines, specifically forms of granulocyte macrophage colony-stimulating factor or granulocyte colony-stimulating factor, to treat radiation-induced myelosuppression. BARDA has supported late-stage development or procurement of Neupogen (filgrastim), Neulasta (pegfilgrastim), and Leukine (sargramostim). Two of these products, Neupogen and Neulasta, have received FDA approval for the treatment of radiation-induced myelosuppression based, in part, upon efficacy shown in nonhuman primate models [10, 11] CID 2017:64 (15 May) Larsen and Disbrow

4 All 3 cytokines are commercial products that are used to treat the myelosuppressive effects of chemotherapy and other cancer treatments. The cytokines that BARDA has procured are held under vendor-managed inventory, with the manufacturers holding a specific inventory of product in the event of a public health emergency, but rotating the product into the commercial market as needed. This allows for reduced footprint and cost for the Strategic National Stockpile and represents an example of an innovative approach that BARDA has taken to partnering with industry to achieve preparedness objectives. Another component of the public health emergency response to a radiological or nuclear event is the need to treat caused by cutaneous radiation or direct exposure to thermal energy. BARDA supported the late-stage development of a suite of products that have the potential to transform the standard of care for burn patients, while also stockpiling those products for use in a public health emergency. BARDA has stockpiled Silverlon, a silver-impregnated wound dressing that does not require repeated application and removal as is the case for silver sulfadiazine cream [12]. BARDA also is supporting the development and procurement of NexoBrid, a novel nonsurgical enzymatic debriding agent that dissolves the burn wound eschar. This technology would allow for the establishment of a clean wound bed suitable for skin grafting and reduce the need for the removal of excess healthy tissue, thereby improving patient outcomes [13]. Another critical component of burn care is the grafting of skin to the wound site. This normally involves the surgical removal of skin from another undamaged site. Technologies that could reduce or minimize the amount of skin taken from the donor site would decrease patient discomfort and potential further risk. BARDA is supporting ReCell, an innovative treatment device that allows for autograft sparing, decreasing the amount of skin that is harvested from the donor site. A small sample of skin is collected and processed to form a regenerative epithelial suspension that is sprayed onto the burn wound. The solution contains all of the required elements for skin growth and regeneration, allowing for improved patient outcomes [14]. Last, BARDA is supporting the development and procurement of an artificial skin substitute. StrataGraft is a regenerative skin tissue that is being developed for severe [15]. If successful, StrataGraft will eliminate the need for autografting from donor sites in patients, reduce patient pain, and generate faster healing times and shorter hospital stays for patients. Collectively, these technologies will allow for an improved standard of care for burn wounds and could be more readily implemented into the healthcare setting during a public health emergency. In its first decade, BARDA, under the auspices of Project BioShield, has improved the capability to respond to and mitigate the effects of multiple threat agents. The combination and quantity of medical countermeasures for anthrax, smallpox, and botulism position the United States to be better prepared and respond to the majority of probable, high-consequence scenarios that might occur. These capabilities serve as a substantial deterrent to actors who would choose to select these agents for an attack. For other threats, such as radiation and chemical agents, BARDA has developed capabilities that were nonexistent 5 years ago. For example, we now possess the capability to detect radiation exposure and treat its initial effects on the body. Going forward, new capabilities to respond to additional threats will need to be developed. The outbreak of Ebola in West Africa has highlighted the devastation resulting from a highly pathogenic virus outbreak in more a densely populated urban center. Vaccines and therapeutics that were rapidly advanced in development during the outbreak will now need sustained support and market incentives to ensure those products reach FDA approval and commercialization. Ebola virus, and other viral hemorrhagic fever viruses (VHFs) like Marbug and Sudan, have been identified as material threats to the United States and, therefore, countermeasures for these threats are eligible for support under Project BioShield. Therefore, the US government will continue to support vaccines, therapeutics, and diagnostics to address a potential terrorist threat or the next natural VHF outbreak. Antimicrobial-resistant bacterial infections also represent a profound threat to public health [16]. BARDA has successfully built a robust portfolio of antibiotic candidates and has progressed several into phase 3 clinical development. BARDA also launched CARB-X, a novel global partnership aimed at promoting innovation in antibacterial drug development [17]. The current economics of antibacterial drug development are very challenging [18]. It is generally acknowledged that in addition to push incentives that lower the cost of development, a robust pull incentive that provides a known return on investment is needed to get companies to invest in developing new antibacterial drugs. Project BioShield has served as a strong pull incentive for companies developing biodefense products. When combined with push incentives supported by BARDA s advanced research and development program, it has been an extremely effective tool at building a medical countermeasure pipeline and keeping companies engaged in the development and commercialization of these products. Increasingly, there is discussion of the adoption of alternative market models that reward innovation but de-link the return on investment of an antibiotic from the volume sold [19]. The decade of BARDA s experience administering both push and pull incentives could be adapted to support alternative market models, such as de-linkage, for antibiotics. While BARDA and Project BioShield have greatly improved preparedness, the program does have its limitations. In its original form, Project BioShield was appropriated $5.8 billion over a 10-year period. It was not subject to annual appropriations from the US Congress. The current $2.8 billion that was authorized from 2014 to 2018 under PAHPRA is annually appropriated. Project BioShield and BARDA: 10-Year Progress Report CID 2017:64 (15 May) 1433

5 To date, BARDA has been appropriated a fraction of that funding. Overall, planning complex medical countermeasure procurements is made much more challenging when one cannot reliably predict the level of funding from year to year. Further, many companies incentivized to work on medical countermeasures for CBRN threats do not have products that can be sold in the commercial marketplace. Typically, the pipeline of products in development is limited. Thus, it becomes difficult to sustain companies that are developing these products when the majority of their revenues are directly tied to procurements by the US government. Further, the support of more than one company developing a specific medical countermeasure spurs competition, which in turn fuels innovation and reduces price. However, it is also very difficult to support multiple companies that are dependent on US government procurements to sustain their commercial viability. A balance must be struck in incentivizing companies in a way that promotes innovation but ensures reasonable prices for the government and is sustainable in the long term. Another challenge faced by developers of medical countermeasures is the uncertainty of how or where their products might be used. It is increasingly recognized that if a CBRN event were to occur internationally, products that have been stockpiled under Project BioShield may be used in the response. This raises issues of liability and uncertainty of the use of those experimental products. Developers of products used in the United States, or overseas on US soil, under Emergency Use Authorization are indemnified from potential legal action under the Public Readiness and Emergency Preparedness Act (PREP) [20]. Those protections are not extended internationally and may represent a deterrent for those companies who view that liability as too great of a risk. It is likely that indemnification policies could be established in the countries affected by the event, but that would likely be conducted in an ad hoc fashion, during the response itself. Policies that protect developers internationally are needed to facilitate a global response to these threat agents. Despite some limitations, BARDA s experience with incentivizing companies under Project BioShield has resulted in multiple FDA-approved medical countermeasures and products stockpiled for emergency use. These products include biologic therapeutics, small-molecule drugs, vaccines, and diagnostics. Going forward, BARDA will continue to utilize Project BioShield to conduct late-stage development and procurement for medical countermeasures for additional threats. With the emergence of Zika and other viruses of pandemic potential, companies are increasingly faced with the decision to pursue development of candidate products in markets with great uncertainty. Few can readily predict which diseases will emerge, to what degree, and for how long. To ensure sustained preparedness for these threats, different market incentives are needed. BARDA s experience with Project BioShield represents an intriguing starting point for the discussion. Notes Disclaimer. The views expressed are those of the authors and not necessarily those of the Biomedical Advanced Research and Development Authority, the Assistant Secretary of Preparedness and Response, or the United States Department of Health and Human Services. Potential conflicts of interest. Both authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. White House. President Bush signs Project BioShield Act of Available at: georgewbush-whitehouse.archives.gov/news/releases/2004/07/ html. 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Burns 2014; 40: Sood R, Roggy DE, Zieger MJ, Nazim M, Hartman BC, Gibbs JT. A comparative study of spray keratinocytes and autologous meshed split-thickness skin graft in the treatment of acute burn injuries. Wounds 2015; 27: Schurr MJ, Foster KN, Centanni JM, et al. Phase I/II clinical evaluation of StrataGraft: a consistent, pathogen-free human skin substitute. J Trauma 2009; 66:866 73; discussion Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States. Available at: Accessed 19 November Outterson K, Rex JH, Jinks T, et al. Accelerating global innovation to address antibacterial resistance: introducing CARB-X. Nat Rev Drug Discov 2016; 15: Sciaretta K, Rottingen JA, Opalska A, Larsen J. Economic incentives for antibacterial drug development: literature review and considerations by the Transatlantic Task Force on Antimicrobial Resistance. Clin Infect Dis 2016; 63: Rex JH, Outterson K. 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