The Medical Countermeasures against Radiation Consortium (CMCRC) is a network of national research centers working together to develop effective and comprehensive medical countermeasures applicable to all subsets of the civilian population in the event of radiological or nuclear emergencies. They utilize multidisciplinary basic and translational research to support the development of new medical products that will assess, diagnose, mitigate and/or treat the short- and long-term consequences of radiation exposure after a radiological/nuclear terrorist event or accidental exposure. The goals of the CMCRC are to: 1) produce new techniques and devices to measure radiation exposure in the human body; 2) follow biomarkers of tissue damage and recovery; and 3) develop novel therapies to minimize tissue damage, hasten tissue recovery, restore normal physiological function, and improve survival. This research program was originally established by NIAID in 2005 under RFA-AI-04-045 and has been reissued three more times: 2010 (RFA-AI-09-036), 2015(RFA-AI-14-055), and 2020 (RFA-AI-19-012).
Background
Very few medical products exist that have been shown to counter the acute and long-term injuries that can result from a nuclear or radiological attack or accident. The threat of attack has grown in recent years, with increased activity of global terrorist organizations and a rise in illicit trafficking of radioactive materials. The National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) was given the responsibility by the Department of Health and Human Services (DHHS) to identify, characterize and develop new medical countermeasure products against radiological and nuclear attacks that may cause a public health emergency.
In 2005, the NIH published a Strategic Plan and Research Agenda for Medical Countermeasures against Radiological and Nuclear Threats and in 2012, a Strategic Plan and Research Agenda for Medical Countermeasures against Radiological and Nuclear Threats Progress Report: 2005-2011 and Future Research Directions: 2012 - 2016. The agendas of both documents include product development focused on medical countermeasures for mitigation and treatment of acute radiation syndromes (ARS) and radionuclide decorporation agents, and of biodosimetry platforms. Several NIAID-supported contract and grant programs have been established to expand the medical options available to mitigate and/or treat radiation injury after any radiological/nuclear terrorist attacks or accidents. The CMCR Consortium forms one part of this overall program, providing the early and intermediate stages of the product development pipeline. To date this program has yielded leading candidates for mitigators/therapeutic agents and improved diagnostic tools to assess radiation exposure, which are currently at different stages of maturity. Continued investment into the CMCRC program is needed to fulfill the ultimate goal of supplying the Strategic National Stockpile (SNS) with medical countermeasures, mitigators and/or treatments, biomarker assays and devices to improve survival after acute radiation exposure.
Under normal conditions, the hematopoietic, gastrointestinal, cardiovascular, and central nervous systems as well as skin and mucosal tissues interact with each other to maintain physiological homeostasis. It is clear from data obtained from prior radiological and nuclear accidents that these homeostatic mechanisms may be severely disturbed due to the compromise and progressive physiological failure of these interdependent organ systems, potentially leading to multiple organ failure and mortality. The management of radiation casualties with multi-organ dysfunction syndrome is extremely complex and effective medical countermeasures are lacking. Therefore, there is an urgent need to develop clinical tools and new treatment strategies to treat multiple organ failure and restore physiological functions of critical organs after exposure.
Finally, a significant burden of radiation-associated morbidity and mortality is attributable to the delayed and late effects of acute radiation exposure (DEARE), including persistent systemic inflammation, accelerated immune aging, lung fibrosis and pneumonitis, and increased frequency of cardiovascular and metabolic diseases. The understanding and elucidation of DEARE are thus important to inform public health officials on future medical resources and capabilities that may be needed in the years and decades following a public radiation emergency.
Predicting the severity and specific manifestations of injury in irradiated individuals is also complex. Radiation injury can take days or weeks to present clinical manifestations, and some delayed radiation injuries (such as fibrosis) may not manifest clinically for months or years. Moreover, individuals may differ in their sensitivity to radiation for a variety of reasons, including age, body size, immune status, and genetic background. Finally, the severity of injury to individual organs and tissues varies with radiation dose rate, quality of radiation (low versus high linear energy transfer), the heterogeneity of exposure (partial versus total body), the source of exposure (external radiation versus internal contamination), and could conceivably be modulated by such factors as the bystander effect and the host’s adaptive response to prior radiation exposure. Unfortunately, existing biodosimetry techniques and devices have limited, if any, ability to discriminate such variables and they do not predict the severity of injury sustained by specific organs and tissues. Diagnostics that take account of such variables would facilitate the prompt organ- and tissue-directed medical treatment that might be provided by future medical countermeasures. Therefore, in addition to radiation dose assessment through biodosimetry tools and techniques, there is a critical unmet need to develop radiation-exposure biomarkers and devices that will predict the early and/or delayed damage to specific organs and tissues to facilitate precise and timely medical intervention, reduce morbidity, and save lives.
The overarching goal of the CMCRC is to address these unmet needs through an organizational framework of multidisciplinary extramural research centers, consisting of academic, commercial, and/or eligible government laboratories. The specific objectives are to use basic and translational research to develop improved diagnostic tools to assess radiation exposure and biomarker assays of acute radiation injury to different organs/tissues; identify new countermeasures; develop and validate new animal models or in vitro assays to evaluate countermeasures or underlying biology; and move candidate countermeasures through the FDA regulatory process to facilitate eventual licensure and potential inclusion in the SNS. Candidate products with mitigation or treatment potential will be moved into characterization and investigational new drug (IND)-enabling, licensing studies such as those conducted by the NIAID’s Product Development Support Services contract (i.e., formulation development, proof of concept studies, and toxicology and efficacy studies to optimize formulation, dose, and dose scheduling) to facilitate eventual FDA licensure and potential inclusion in the SNS.
Research Objectives and Scope
The overall goal of this program is the development and maintenance of a strong infrastructure, combined with the multidisciplinary research expertise and development capacity to generate new medical products that will protect against, mitigate the effects of, and treat the acute-, short-, and long-term consequences of radiation exposure from terrorist attacks or accidental exposure. To realize this goal, the CMCRC will support: 1) basic, translational, or applied research; 2) development and utilization and/or expansion of existing core facilities that support the research and development activities of an individual center; 3) utilization or development of translational research capacity to test and characterize radiation countermeasures for regulatory approvals; and 4) provide training and education materials in radiobiology research. Diverse research and development approaches are encouraged, but all projects must focus on medical countermeasures to mitigate or treat human injury incurred by radiological or nuclear attacks or accidents, or improved diagnostic tools to assess radiation exposure and must describe their feasibility for human use under public health emergency conditions. Although clinical research is encouraged within this program where relevant, clinical trials will not be supported.
The CMCRC will consist of a consortium of centers focused on accelerating the development and production of medical countermeasures against radiological or nuclear exposure of the civilian population.
This program is milestone-based, and includes the flexibility to quickly redirect or replace research projects during the funding period.
Within the Consortium, current candidate products with mitigation or treatment potential may be moved into validation and licensing studies to facilitate their inclusion in the SNS. The program will support applied research and studies to advance products through needed developmental stages when proposed by applicants with these capabilities. The program will also promote confirmatory screening studies, leading to the submission of an investigational new drug (IND) application to the Food and Drug Administration (FDA) to facilitate eventual licensure and potential inclusion in the SNS including: 1) toxicology and efficacy studies consistent with Good Laboratory Practice (GLP) to test proof of concept, determine test article safety and to optimize formulation, dose, and dose scheduling; and 2) steps related to formulation development, manufacturing, and drug stability consistent with current Good Manufacturing Practices (cGMP). All grantees are strongly encouraged to confer with the NIAID staff and with staff at the U.S. FDA as soon as an appropriate product candidate or medical approach is identified.
Organization of the CMCRC
The CMCRC consists of 3 Centers (each with a minimum of three research projects, one Administrative Core and optional Service Cores), four Consortium Cores (Coordinating Center Core, Opportunities Fund Management Core, Radiation Physics Core, and Radiation Survivor Core - all administered by institutions selected by the NIAID from the successful applicants), a Steering Committee and its subcommittees, a Consortium External Advisory Committee (CEAC), and other committees as needed.
Center Components
Administrative Core
The Administrative Core supports the coordination of efforts across the research projects and Service Cores, and will support activities to advance integration into the broader CMCRC. This core will be responsible for organization, management, decision-making, and periodic evaluations within the individual center, as well as protection of intellectual property, regulatory compliance, involvement of institutional and programmatic resources, and shared publications. This core is expected to create and implement administrative and leadership mechanisms that will foster effective interactions with other CMCRC PDs/PIs and institutions as well as within the individual group to promote synergistic research efforts. Each center may select an External Scientific Advisory Group (ESAG) to help guide the center’s overall program and monitor research progress.
Service Core(s)
Service Cores provide clinical, statistical, technical, or other supportive activities, including the development of standard assays, reagents and technologies, the establishment and maintenance of repositories, the delivery of statistical, bioinformatics or any other services required to achieve the research/development goals of the program.
Research Projects
Research Projects must be multi-disciplinary, synergistic research/development projects focused on product development as an ultimate goal, even if development of licensed products will not be completed within the funding period. Basic discovery or mechanistic research is allowed, but it must contribute to the development of a product.
Consortium Components
Coordinating Center Core (CCC)
The CCC will be responsible for facilitating the administration, data and information sharing within the CMCRC and the research community, as well as organizing and maintaining web-based educational activities. Activities of the CCC will be undertaken with input from and cooperation with NIAID, the Steering Committee and the CEAC.
Opportunities Fund Management Core (OFMC)
This FOA will provide support for: 1) Pilot Projects and 2) Candidate Medical Countermeasure (MCM) development. Pilot project funding is intended to foster novel ideas within and outside the CMCRC, to develop or incorporate new technologies as they become available, and to encourage collaborations among members of different centers and between the CMCRC and investigators within and outside the US. The use of Pilot Projects permits maximum flexibility to advance in the directions that seem most scientifically fruitful. Pilot projects must be within the scope of the FOA. The funding for candidate MCM development is intended to provide additional assistance and/or technical expertise for IND-enabling studies and candidate MCM product development activities in support of projects undertaken by CMCRC investigators.
Radiation Physics Core (RPC)
The RPC will be responsible for providing consortium-wide standards for the various research sites and sources used to conduct studies on irradiated animals to ensure that all such work conducted within the CMCRC is performed under standardized methodologies. The RPC leader will work with his or her counterparts at other centers to assure consistency of the procedures used to irradiate animals and dosimetry to determine that the desired radiation dose is delivered in the proscribed manner.
Radiation Survivor Core (RSC)
The RSC will be responsible for the clinical and pathologic assessment of humans and non-human primates (NHP) previously exposed to radiation.
Steering Committee (SC)
A Steering Committee will serve as the governing board and will coordinate and facilitate research activities for the overall program and foster synergy and efficiency within the Consortium. In addition, the Steering Committee will determine policies and implement processes for quality assurance of any data and information disseminated through activities of the CCC. The Steering Committee will also be responsible for establishing and implementing a process for selection of activities for funding with discretionary funds through the OFMC.
Consortium External Advisory Committee (CEAC)
The NIAID will appoint a CEAC of 3-5 members. This group will be updated on progress and inform the Steering Committee and the NIAID on adjustments and future directions for the CMCRC research projects and shared consortium cores.
