Development of Radiation/Nuclear Medical Countermeasures (MCMs) And Biodosimetry Devices

Radiological/nuclear incidents can potentially result in the exposure of large numbers of civilians to a high dose of radiation in a short period of time. Depending on the dose and proportion of wholebody exposure to external radiation, biological effects can range from acute complications (acute radiation syndrome, ARS), including nausea and vomiting within hours; hematopoietic and gastrointestinal (GI) injuries leading to immunosuppression, infections, hemorrhage, and death within days to weeks; to delayed effects of acute radiation exposure (DEARE) in ARS survivors, including cutaneous, pulmonary, cardiovascular, central nervous system, or renal complications months to years after irradiation.

The U.S. Government recognizes the need to develop medical countermeasures (MCMs) (e.g., drugs, biologics, cell, or cell products) and biodosimetry devices to address radiation-induced biological injuries sustained during a radiological or nuclear incident. To this end, the Project BioShield Act of 2004, Public Law 108-276, was enacted. This Act provides the Department of Health and Human Services (HHS) with authorities to procure MCMs for the Strategic National Stockpile (SNS) and to perform advanced research and development on priority MCMs against chemical, biological, radiological, and nuclear threats. Under this act, the Radiation and Nuclear Countermeasures Program (RNCP) within NIAID was created and charged by HHS, on behalf of the
National Institutes of Health (NIH), to address radiation-induced injuries resulting from a radiation public health emergency, with funds provided to the NIH from a special congressional appropriation.

The coordinated efforts to support radiation research and development by the NIH, as well as other HHS agencies, are outlined in the HHS Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy and Implementation Plan. The NIH is committed to accelerating the development of drugs and biologics to treat radiation injuries and for triage use in mass casualty
situations. NIAID/RNCP supports advanced development efforts to make these MCMs available for possible procurement by the Biomedical Advanced Research and Development Authority (BARDA) and subsequent storage in the SNS, under the aegis of the Administration for Strategic Preparedness and Response (ASPR).

The RNCP manages a multifaceted program to expand research infrastructure and radiobiology expertise; promote research and development of biodosimetry methods to assess radiation injury; and identify, develop, and obtain approval/licensure for MCMs to mitigate and/or treat radiationinduced injuries. Six MCMs have been approved by the U.S. Food and Drug Administration (FDA)
for hematopoietic ARS (H-ARS) to increase survival in patients acutely exposed to myelosuppressive doses of radiation, and one product has FDA clearance as a device to treat cutaneous radiation injury. However, no biodosimetry approach has yet been cleared by the FDA for use in triage or as a diagnostic tool to assess potentially irradiated individuals.

The goals of this BAA are two-fold. The first goal is to develop safe and effective MCMs to mitigate and/or treat normal tissue injuries arising from exposure to ionizing radiation from a radiological or nuclear incident, thereby leading to a reduction in radiation-associated mortality and/or major morbidities. MCMs are not expected to be effectively mobilized for use within the first day; therefore, MCMs must be efficacious 24 hours or later post-exposure (except as noted below). The second goal is to advance biodosimetry biomarkers and/or devices to inform triage and treatment strategies for use during a radiation public health emergency. Proposals must only address one goal; if the offeror intends to address both goals, two separate proposals must be submitted - one
addressing MCM development and the other addressing biodosimetry.

MCMs

Since program inception, the RNCP/NIAID has sponsored early-stage/applied research, product development programs, and targeted initiatives focused on development of drugs to mitigate or treat complications of ARS and DEARE. Investment in this portfolio has led to the establishment of several rodent, swine, and nonhuman primate animal models, which are critical for licensure of radiation mitigators under the U.S. FDA Animal Rule. Studies funded by the RNCP led to FDA approval of Neupogen® (filgrastim, 2015), Neulasta® (pegfilgrastim, 2015) and Nplate® (romiplostim, 2021), whereas support from other parts of HHS led to approval of Leukine® (sargramostim). The Neulasta biosimilars, Udenyca®, Stimufend® and Ziextenzo®, also were approved on November 11, 2022, September 29, 2023 and February 2024, respectively. The Neupogen biosimilars, Nypozi® and Zarxio®, were approved in June and October 2024, respectively. Although progress has been made in licensing products to treat H-ARS, drugs are still needed to address radiation injury to other organ systems affected by radiation exposure, such as the GI tract, lung, skin, kidney, cardiovascular, and central nervous systems.

Since there are already nine FDA-approved MCMs for H-ARS, if proposing studies on H-ARS products that target neutropenia or thrombocytopenia, to be considered responsive to the BAA, offerors must demonstrate that these products have advantages over existing FDA-approved H-ARS MCMs (e.g., efficacious when administered at 48 hours post-radiation exposure or later, more advantageous route of administration for mass-casualty scenario, improved mass casualty- amenable storage, etc.).

In addition, MCMs proposed to address radiation injuries to other organ systems (e.g., GI, lung, vascular, kidney, cardiac, central nervous system, etc.) are encouraged to include candidate product treatment arms in the presence and absence of an approved H-ARS MCM, to demonstrate no contraindication with expected standard of care in a mass casualty incident. Note that MCMs to address radiation-induced cancers or cataracts will not be supported by this contract.

Biodosimetry Biomarkers/Devices
In a mass casualty radiation incident, victims may have different sensitivities to radiation and might not initially show clear signs and symptoms of radiation toxicity, even if exposed to substantial doses of radiation. Similarly, persons exposed to a radiological dispersal device (i.e., a “dirty bomb”) may only present minimal symptoms at time of exposure but may suffer from delayed adverse radiation injuries. Confounding factors that could account for person-to-person variability include, but are not limited to sex, genetic pre-disposition, age, body size, underlying illnesses, and immune status. Therefore, estimates of radiation exposure dose alone will not necessarily predict the extent of radiation injury to organs and tissues, underscoring the need for rapid, accurate, and sensitive biomarker assays/techniques and diagnostic platforms that can confirm exposure and/or predict acute and delayed radiation injuries to major organs.

Existing “gold standard” biodosimetry techniques (e.g., dicentric chromosomal aberration assay) do not necessarily assess biological variability or inhomogeneous exposures, nor can they predict the severity/outcome of injury sustained by specific organs and tissues. Therefore, development of biodosimetry tools targeting radiation-specific biomarkers that will determine and/or predict acute and/or delayed damage to specific organs and tissues (i.e., predictive biodosimetry) beyond dose assessment also is needed. Assessment of such biomarkers will facilitate precise and timely medical interventions, reduce morbidities, and save lives. Biodosimetry will specifically address the following unmet needs: 1) distinguish between concerned citizens (who have not been exposed) and those who have been exposed, 2) estimate radiation dose in the affected group, and/or 3) predict acute and delayed radiation injuries to major organs/physiological systems in the event of a large-scale radiation incident.