Product Development within the National Institutes of Health Radiation and Nuclear Countermeasures Program.

The Radiation and Nuclear Countermeasures Program (RNCP) at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) was established to facilitate the development of medical countermeasures (MCMs) and diagnostic approaches for use in a radiation public health emergency. Approvals for MCMs can be very challenging but are made possible under the United States Food and Drug Administration (FDA) Animal Rule, which is designed to enable licensure of drugs or biologics when clinical efficacy studies are unethical or unfeasible. The NIAID portfolio includes grants, contracts, and inter-agency agreements designed to span all aspects of drug development and encompasses basic research through FDA approval. In addition, NIAID manages an active portfolio of biodosimetry approaches to assess injuries and absorbed radiation levels to guide triage and treatment decisions. NIAID, together with grantees, contractors, and other stakeholders with promising products, works to advance candidate MCMs and biodosimetry tools through an established product development pipeline. In addition to managing grants and contracts, NIAID tests promising candidates in our established preclinical animal models, and the NIAID Program Officers work closely with sponsors as product managers to guide them through the process. In addition, a valuable benefit for stakeholders is working with the NIAID Office of Regulatory Affairs, where NIAID coordinates with the FDA to facilitate interactions between sponsors and the agency. Activities funded by NIAID include basic research (e.g., library screens to discover new products, determine early efficacy, and delineate mechanism of action) and the development of small and large animal models of radiation-induced hematopoietic, gastrointestinal, lung, kidney, and skin injury, radiation combined injury, and radionuclide decorporation. NIAID also sponsors Good Laboratory Practice product safety, pharmacokinetic, pharmacodynamic, and toxicology studies, as well as efficacy and dose-ranging studies to optimize product regimens. For later-stage candidates, NIAID funds large-scale manufacturing and formulation development of products. The program also supports Phase 1 human clinical studies to ensure human safety and to bridge pharmacokinetic, pharmacodynamic, and efficacy data from animals to humans. To date, NIAID has supported >900 animal studies and one clinical study, evaluating >500 new/repurposed radiation MCMs and biodosimetric approaches. NIAID sponsorship led to the approval of three of the six drugs for acute radiation syndrome under the FDA Animal Rule, five Investigational New Drug applications, and 18 additional submissions for Investigational Device Exemptions, while advancing 38 projects to the Biomedical Advanced Research and Development Authority for follow-on research and development.

Radiation-induced multi-organ injury.

PURPOSE: Natural history studies have been informative in dissecting radiation injury, isolating its effects, and compartmentalizing injury based on the extent of exposure and the elapsed time post-irradiation. Although radiation injury models are useful for investigating the mechanism of action in isolated subsyndromes and development of medical countermeasures (MCMs), it is clear that ionizing radiation exposure leads to multi-organ injury (MOI). METHODS: The Radiation and Nuclear Countermeasures Program within the National Institute of Allergy and Infectious Diseases partnered with the Biomedical Advanced Research and Development Authority to convene a virtual two-day meeting titled 'Radiation-Induced Multi-Organ Injury' on June 7-8, 2022. Invited subject matter experts presented their research findings in MOI, including study of mechanisms and possible MCMs to address complex radiation-induced injuries. RESULTS: This workshop report summarizes key information from each presentation and discussion by the speakers and audience participants. CONCLUSIONS: Understanding the mechanisms that lead to radiation-induced MOI is critical to advancing candidate MCMs that could mitigate the injury and reduce associated morbidity and mortality. The observation that some of these mechanisms associated with MOI include systemic injuries, such as inflammation and vascular damage, suggests that MCMs that address systemic pathways could be effective against multiple organ systems.

Immune Dysfunction from Radiation Exposure.

The hematopoietic system is highly sensitive to ionizing radiation. Damage to the immune system may result in opportunistic infections and hemorrhage, which could lead to mortality. Inflammation triggered by tissue damage can also lead to additional local or widespread tissue damage. The immune system is responsible for tissue repair and restoration, which is made more challenging when it is in the process of self-recovery. Because of these challenges, the Radiation and Nuclear Countermeasures Program (RNCP) and the Basic Immunology Branch (BIB) under the Division of Allergy, Immunology, and Transplantation (DAIT) within the National Institute of Allergy and Infectious Diseases (NIAID), along with partners from the Biomedical Advanced Research and Development Authority (BARDA), and the Radiation Injury Treatment Network (RITN) sponsored a two-day meeting titled Immune Dysfunction from Radiation Exposure held on September 9-10, 2020. The intent was to discuss the manifestations and mechanisms of radiation-induced immune dysfunction in people and animals, identify knowledge gaps, and discuss possible treatments to restore immune function and enhance tissue repair after irradiation.

Immune Dysfunction from Radiation Exposure.

Exposure to ionizing radiation causes acute damage and loss of bone marrow and peripheral immune cells that can result in high mortality due to reduced resistance to infections and hemorrhage. Besides these acute effects, tissue damage from radiation can trigger inflammatory responses, leading to progressive and chronic tissue damage by radiation-induced loss of immune cell types that are required for resolving tissue injuries. Understanding the mechanisms involved in radiation-induced immune system injury and repair will provide new insights for developing medical countermeasures that help restore immune homeostasis. For these reasons, The Radiation and Nuclear Countermeasures Program (RNCP) and the Basic Immunology Branch (BIB) under the Division of Allergy, Immunology, and Transplantation (DAIT) within the National Institute of Allergy and Infectious Diseases (NIAID) convened a two-day workshop, along with partners from the Biomedical Advanced Research and Development Authority (BARDA), and the Radiation Injury Treatment Network (RITN). This workshop, titled "Immune Dysfunction from Radiation Exposure," was held virtually on September 9-10, 2020; this Commentary provides a high-level overview of what was discussed at the meeting.

The NIAID/RNCP Biodosimetry Program: An Overview.

Established in 2004, the Radiation and Nuclear Countermeasures Program (RNCP), within the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health has the central mission to advance medical countermeasure mitigators/therapeutics, and biomarkers and technologies to assess, triage, and inform medical management of patients experiencing acute radiation syndrome and/or the delayed effects of acute radiation exposure. The RNCP biodosimetry mission space encompasses: (1) basic research to elucidate novel approaches for rapid and accurate assessment of radiation exposure, (2) studies to support advanced development for US Food and Drug Administration (FDA) clearance of promising triage or treatment devices/approaches, (3) characterization of biomarkers and/or assays to determine degree of tissue or organ dose that can predict outcome of radiation injuries (i.e., organ failure, morbidity, and/or mortality), and (4) outreach efforts to facilitate interactions with researchers developing cutting edge biodosimetry approaches. Thus far, no biodosimetry device has been FDA cleared for use during a radiological/nuclear incident. At NIAID, advancement of radiation biomarkers and biodosimetry approaches is facilitated by a variety of funding mechanisms (grants, contracts, cooperative and interagency agreements, and Small Business Innovation Research awards), with the objective of advancing devices and assays toward clearance, as outlined in the FDA's Radiation Biodosimetry Medical Countermeasure Devices Guidance. The ultimate goal of the RNCP biodosimetry program is to develop and establish accurate and reliable biodosimetry tools that will improve radiation preparedness and ultimately save lives during a radiological or nuclear incident.

Making connections: the scientific impact and mentoring legacy of Dr. John E. Moulder.

PURPOSE: The intent of this mini review is to pay homage to Dr. John E. Moulder's long and successful career in radiation science with the Medical College of Wisconsin. This effort will be done from the perspective of his history of U.S. Government funding for research into the biological pathways involved in radiation-induced normal tissue injuries, especially damage to the kidneys and heart, and pharmacological interventions. In addition, the impact of his steady guidance and leadership in the mentoring of junior scientists, and the development of meaningful collaborations with other researchers will be highlighted. CONCLUSION: Dr. John E. Moulder's contributions to the field of radiation research, through his strong character and reputation, his consistent and dedicated commitment to his colleagues and students, and his significant scientific advances, have been critical to moving the science forward, and will not be forgotten by those who knew him personally or through publications documenting his important work.

Considerations of Medical Preparedness to Assess and Treat Various Populations During a Radiation Public Health Emergency.

During a radiological or nuclear public health emergency, given the heterogeneity of civilian populations, it is incumbent on medical response planners to understand and prepare for a potentially high degree of interindividual variability in the biological effects of radiation exposure. A part of advanced planning should include a comprehensive approach, in which the range of possible human responses in relation to the type of radiation expected from an incident has been thoughtfully considered. Although there are several reports addressing the radiation response for special populations (as compared to the standard 18-45-year-old male), the current review surveys published literature to assess the level of consideration given to differences in acute radiation responses in certain sub-groups. The authors attempt to bring clarity to the complex nature of human biology in the context of radiation to facilitate a path forward for radiation medical countermeasure (MCM) development that may be appropriate and effective in special populations. Consequently, the focus is on the medical (as opposed to logistical) aspects of preparedness and response. Populations identified for consideration include obstetric, pediatric, geriatric, males, females, individuals of different race/ethnicity, and people with comorbidities. Relevant animal models, biomarkers of radiation injury, and MCMs are highlighted, in addition to underscoring gaps in knowledge and the need for consistent and early inclusion of these populations in research. The inclusion of special populations in preclinical and clinical studies is essential to address shortcomings and is an important consideration for radiation public health emergency response planning. Pursuing this goal will benefit the population at large by considering those at greatest risk of health consequences after a radiological or nuclear mass casualty incident.

NIH Policies and Regulatory Pathways to U.S. FDA licensure: Strategies to Inform Advancement of Radiation Medical Countermeasures and Biodosimetry Devices.

The Radiation and Nuclear Countermeasures Program within the National Institute of Allergy and Infectious Diseases (NIAID), is tasked with the mandate of identifying biodosimetry tests to assess exposure and medical countermeasures (MCMs) to mitigate/treat injuries to individuals exposed to significant doses of ionizing radiation from a radiological/nuclear incident, hosted. To fulfill this mandate, the Radiation and Nuclear Countermeasures Program (RNCP), hosted a workshop in 2018 workshop entitled "Policies and Regulatory Pathways to U.S. FDA licensure: Radiation Countermeasures and Biodosimetry Devices." The purpose of the meeting was to facilitate the advancement of MCMs and biodosimetry devices by assessing the research devices and animal models used in preclinical studies; government policies on reproducibility, rigor and robustness; regulatory considerations for MCMs and biodosimetry devices; and lessons learned from sponsors of early stage MCM or biodosimetry devices. Meeting presentations were followed by a NIAID-led, open discussion among academic investigators, industry researchers and U.S. government representatives.

A Trans-Agency Workshop on the Pathophysiology of Radiation-Induced Lung Injury.

Research and development of medical countermeasures (MCMs) for radiation-induced lung injury relies on the availability of animal models with well-characterized pathophysiology, allowing effective bridging to humans. To develop useful animal models, it is important to understand the clinical condition, advantages and limitations of individual models, and how to properly apply these models to demonstrate MCM efficacy. On March 20, 2019, a meeting sponsored by the Radiation and Nuclear Countermeasures Program (RNCP) within the National Institute of Allergy and Infectious Diseases (NIAID) brought together medical, scientific and regulatory communities, including academic and industry subject matter experts, and government stakeholders from the Food and Drug Administration (FDA) and the Biomedical Advanced Research and Development Authority (BARDA), to identify critical research gaps, discuss current clinical practices for various forms of pulmonary damage, and consider available animal models for radiation-induced lung injury.

A Trans-Agency Workshop on the Pathophysiology of Radiation-Induced Lung Injury.

As of January 2021, the U.S. Food and Drug Administration has approved four radiation exposure medical countermeasures (MCMs) to treat hematological acute effects, but no MCM is yet approved for radiation-induced lung injury (RILI). MCM approval for RILI and other subsyndromes utilizes the FDA Animal Efficacy Rule (Animal Rule), that requires demonstration of MCM efficacy in animal models with well-characterized pathophysiology, therefore, allowing translation to human use. A good animal model replicates the clinical condition and natural history of the disease, while allowing for studying the mechanism of action of the applied MCM and exhibiting clear benefits in terms of primary and secondary endpoints. However, there is much conversation regarding the advantages and limitations of individual models, and how to properly apply these models to demonstrate MCM efficacy. On March 20, 2019, the Radiation and Nuclear Countermeasures Program (RNCP) within the National Institute of Allergy and Infectious Diseases (NIAID), Food and Drug Administration (FDA), and the Biomedical Advanced Research and Development Authority (BARDA) sponsored a workshop to identify critical research gaps, discuss current clinical practices for different types of pulmonary diseases, and consider available animal models for RILI.

Meeting Report: A Poly-Pharmacy Approach to Mitigate Acute Radiation Syndrome.

The National Institute of Allergy and Infectious Diseases, Radiation and Nuclear Countermeasures Program, was tasked by the United States Congress and the U.S. Department of Health and Human Services to identify and fund early-to-mid-stage development of medical countermeasures (MCMs) to treat radiation-induced injuries. In developing MCMs to treat various sub-syndromes (e.g., hematopoietic, gastrointestinal, lung), it is important to investigate whether a poly-pharmacy approach (i.e., drug cocktails) can provide additive benefits to mitigate injuries arising from the acute radiation syndrome (ARS). In addition, potential drug-drug interactions must be examined. For this reason, a workshop was held, which centered on understanding the current state of research investigating poly-pharmacy approaches to treat radiation injuries. The first session set the stage with an introduction to the concept of operations or support available for the response to a nuclear incident, as this is the key to any emergency response, including MCM availability and distribution. The second session followed the natural history of ARS in both humans and animal models to underscore the complexity of ARS and why a poly-pharmacy approach may be necessary. The third session featured talks from investigators conducting current MCM poly-pharmacy research. The meeting closed with a focus on regulatory considerations for the development of poly-pharmacy approaches or combination treatments for ARS.

Acute Radiation Syndrome and the Microbiome: Impact and Review.

Study of the human microbiota has been a centuries-long endeavor, but since the inception of the National Institutes of Health (NIH) Human Microbiome Project in 2007, research has greatly expanded, including the space involving radiation injury. As acute radiation syndrome (ARS) is multisystemic, the microbiome niches across all areas of the body may be affected. This review highlights advances in radiation research examining the effect of irradiation on the microbiome and its potential use as a target for medical countermeasures or biodosimetry approaches, or as a medical countermeasure itself. The authors also address animal model considerations for designing studies, and the potential to use the microbiome as a biomarker to assess radiation exposure and predict outcome. Recent research has shown that the microbiome holds enormous potential for mitigation of radiation injury, in the context of both radiotherapy and radiological/nuclear public health emergencies. Gaps still exist, but the field is moving forward with much promise.

Commonalities Between COVID-19 and Radiation Injury.

As the multi-systemic components of COVID-19 emerge, parallel etiologies can be drawn between SARS-CoV-2 infection and radiation injuries. While some SARS-CoV-2-infected individuals present as asymptomatic, others exhibit mild symptoms that may include fever, cough, chills, and unusual symptoms like loss of taste and smell and reddening in the extremities (e.g., "COVID toes," suggestive of microvessel damage). Still others alarm healthcare providers with extreme and rapid onset of high-risk indicators of mortality that include acute respiratory distress syndrome (ARDS), multi-organ hypercoagulation, hypoxia and cardiovascular damage. Researchers are quickly refocusing their science to address this enigmatic virus that seems to unveil itself in new ways without discrimination. As investigators begin to identify early markers of disease, identification of common threads with other pathologies may provide some clues. Interestingly, years of research in the field of radiation biology documents the complex multiorgan nature of another disease state that occurs after exposure to high doses of radiation: the acute radiation syndrome (ARS). Inflammation is a key common player in COVID-19 and ARS, and drives the multi-system damage that dramatically alters biological homeostasis. Both conditions initiate a cytokine storm, with similar pro-inflammatory molecules increased and other anti-inflammatory molecules decreased. These changes manifest in a variety of ways, with a demonstrably higher health impact in patients having underlying medical conditions. The potentially dramatic human impact of ARS has guided the science that has identified many biomarkers of radiation exposure, established medical management strategies for ARS, and led to the development of medical countermeasures for use in the event of a radiation public health emergency. These efforts can now be leveraged to help elucidate mechanisms of action of COVID-19 injuries. Furthermore, this intersection between COVID-19 and ARS may point to approaches that could accelerate the discovery of treatments for both.

Study logistics that can impact medical countermeasure efficacy testing in mouse models of radiation injury.

PURPOSE: To address confounding issues that have been noted in planning and conducting studies to identify biomarkers of radiation injury, develop animal models to simulate these injuries, and test potential medical countermeasures to mitigate/treat damage caused by radiation exposure. METHODS: The authors completed an intensive literature search to address several key areas that should be considered before embarking on studies to assess efficacy of medical countermeasure approaches in mouse models of radiation injury. These considerations include: (1) study variables; (2) animal selection criteria; (3) animal husbandry; (4) medical management; and (5) radiation attributes. RESULTS: It is important to select mouse strains that are capable of responding to the selected radiation exposure (e.g. genetic predispositions might influence radiation sensitivity and proclivity to certain phenotypes of radiation injury), and that also react in a manner similar to humans. Gender, vendor, age, weight, and even seasonal variations are all important factors to consider. In addition, the housing and husbandry of the animals (i.e. feed, environment, handling, time of day of irradiation and animal restraint), as well as the medical management provided (e.g. use of acidified water, antibiotics, routes of administration of drugs, consideration of animal numbers, and euthanasia criteria) should all be addressed. Finally, the radiation exposure itself should be tightly controlled, by ensuring a full understanding and reporting of the radiation source, dose and dose rate, shielding and geometry of exposure, while also providing accurate dosimetry. It is important to understand how all the above factors contribute to the development of radiation dose response curves for a given animal facility with a well-defined murine model. CONCLUSIONS: Many potential confounders that could impact the outcomes of studies to assess efficacy of a medical countermeasure for radiation-induced injuries are addressed, and recommendations are made to assist investigators in carrying out research that is robust, reproducible, and accurate.

Metabolomics in Radiation Biodosimetry: Current Approaches and Advances.

Triage and medical intervention strategies for unanticipated exposure during a radiation incident benefit from the early, rapid and accurate assessment of dose level. Radiation exposure results in complex and persistent molecular and cellular responses that ultimately alter the levels of many biological markers, including the metabolomic phenotype. Metabolomics is an emerging field that promises the determination of radiation exposure by the qualitative and quantitative measurements of small molecules in a biological sample. This review highlights the current role of metabolomics in assessing radiation injury, as well as considerations for the diverse range of bioanalytical and sampling technologies that are being used to detect these changes. The authors also address the influence of the physiological status of an individual, the animal models studied, the technology and analysis employed in interrogating response to the radiation insult, and variables that factor into discovery and development of robust biomarker signatures. Furthermore, available databases for these studies have been reviewed, and existing regulatory guidance for metabolomics are discussed, with the ultimate goal of providing both context for this area of radiation research and the consideration of pathways for continued development.

Challenges and Benefits of Repurposing Products for Use during a Radiation Public Health Emergency: Lessons Learned from Biological Threats and other Disease Treatments.

The risk of a radiological or nuclear public health emergency is a major growing concern of the U.S. government. To address a potential incident and ensure that the government is prepared to respond to any subsequent civilian or military casualties, the U.S. Department of Health and Human Services and the Department of Defense have been charged with the development of medical countermeasures (MCMs) to treat the acute and delayed injuries that can result from radiation exposure. Because of the limited budgets in research and development and the high costs associated with bring promising approaches from the bench through advanced product development activities, and ultimately, to regulatory approval, the U.S. government places a priority on repurposing products for which there already exists relevant safety and other important information concerning their use in humans. Generating human data can be a costly and time-consuming process; therefore, the U.S. government has interest in drugs for which such relevant information has been established (e.g., products for another indication), and in determining if they could be repurposed for use as MCMs to treat radiation injuries as well as chemical and biological insults. To explore these possibilities, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop including U.S. government, industry and academic subject matter experts, to discuss the challenges and benefits of repurposing products for a radiation indication. Topics covered included a discussion of U.S. government efforts (e.g. funding, stockpiling and making products available for study), as well unique regulatory and other challenges faced when repurposing patent protected or generic drugs. Other discussions involved lessons learned from industry on repurposing pre-license, pipeline products within drug development portfolios. This report reviews the information presented, as well as an overview of discussions from the meeting.

Building the strategic national stockpile through the NIAID Radiation Nuclear Countermeasures Program.

The possibility of a public health radiological or nuclear emergency in the United States remains a concern. Media attention focused on lost radioactive sources and international nuclear threats, as well as the potential for accidents in nuclear power facilities (e.g., Windscale, Three Mile Island, Chernobyl, and Fukushima) highlight the need to address this critical national security issue. To date, no drugs have been licensed to mitigate/treat the acute and long-term radiation injuries that would result in the event of large-scale, radiation, or nuclear public health emergency. However, recent evaluation of several candidate radiation medical countermeasures (MCMs) has provided initial proof-of-concept of efficacy. The goal of the Radiation Nuclear Countermeasures Program (RNCP) of the National Institute of Allergy and Infectious Diseases (National Institutes of Health) is to help ensure the government stockpiling of safe and efficacious MCMs to treat radiation injuries, including, but not limited to, hematopoietic, gastrointestinal, pulmonary, cutaneous, renal, cardiovascular, and central nervous systems. In addition to supporting research in these areas, the RNCP continues to fund research and development of decorporation agents targeting internal radionuclide contamination, and biodosimetry platforms (e.g., biomarkers and devices) to assess the levels of an individual's radiation exposure, capabilities that would be critical in a mass casualty scenario. New areas of research within the program include a focus on special populations, especially pediatric and geriatric civilians, as well as combination studies, in which drugs are tested within the context of expected medical care management (e.g., antibiotics and growth factors). Moving forward, challenges facing the RNCP, as well as the entire radiation research field, include further advancement and qualification of animal models, dose conversion from animal models to humans, biomarker identification, and formulation development. This paper provides a review of recent work and collaborations supported by the RNCP.

Medical countermeasures for platelet regeneration after radiation exposure. Report of a workshop and guided discussion sponsored by the National Institute of Allergy and Infectious Diseases, Bethesda, MD, March 22­23, 2010.

The events of September 11, 2001 and their aftermath increased awareness of the need to develop medical countermeasures (MCMs) to treat potential health consequences of a radiation accident or deliberate attack. The medical effects of lethal exposures to ionizing radiation have been well described and affect multiple organ systems. To date, much of the research to develop treatments for mitigation of radiation-induced hematopoietic damage has focused on amelioration of radiation-induced neutropenia, which has long been considered to be the primary factor in determining survival after an unintentional radiation exposure. Consistent with historical data, recent studies have highlighted the role that radiation-induced thrombocytopenia plays in radiation mortality, yet development of MCMs to mitigate radiation damage to the megakaryocyte lineage has lagged behind anti-neutropenia approaches. To address this gap and to foster research in the area of platelet regeneration after radiation exposure, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored a workshop on March 22-23, 2010 to encourage collaborations between NIAID program awardees and companies developing pro-platelet approaches. NIAID also organized an informal, open discussion between academic investigators, product development contractors, and representatives from the U.S. Food and Drug Administration (FDA) and other relevant government agencies about drug development toward FDA licensure of products for an acute radiation syndrome indication. Specific emphasis was placed on the challenges of product licensure for radiation/nuclear MCMs using current FDA regulations (21 CFR Parts 314 and 601) and on the importance of animal efficacy model development, design of pivotal protocols, and standardization of irradiation and animal supportive care.