Approved MCMs—Decorporation and Blocking Agents

The primary concern of nuclear power plant accidents is the release of radioisotopes into the community. A variety of isotopes may be released, including the fuel (uranium or plutonium), as well as decay products, such as radioactive iodine and cesium.Reference Christodouleas, Forrest, Ainsley, Tochner, Hahn and Glatstein⁶ Blocking agents, such as potassium iodide (KI), prevent the accumulation of an isotope in the target organ. KI was approved by the FDA in 1979 after the Three Mile Island accident.Reference Halperin⁷ The approval was based on available human data from several sources.⁸ KI would be used in a nuclear power plant accident scenario where radioactive iodine release would be a potential concern, as it is used as a post exposure blocking agent to prevent uptake of radioactive iodine into the thyroid, thereby reducing the risk of radioiodine-induced thyroid cancer. There have been several KI products approved by the FDA^9–12 (Table 1), and they represent the earliest approvals for therapeutic interventions in the Rad/Nuc space.

Table 1.

Approved MCMs within the radiological/nuclear space

Table 1. Long description

The table consists of four columns: Product, F D A approval, Animal Rule, and Indication or use.

- Thyro-Block (1979), K I-i O S A T (1982), K I-ThyroSafe (2002), K I-Thyroshield (2005), and K I Oral Solution (2016) are all listed as ‘No’ for Animal Rule. Their shared indication is the prevention of uptake of radioactive iodine into the thyroid post exposure to reduce cancer risk.

- Radiogardase (Prussian blue), approved in 2003, Animal Rule ‘No’, is for treating internal contamination with radioactive cesium or thallium to increase elimination rates.

- C a-D T P A and Z n-D T P A, both approved in 2004, Animal Rule ‘No’, are radiomitigation chelators for internal contamination with plutonium, americium, or curium.

- Neupogen and Neulasta, both approved in 2015, Animal Rule ‘Yes’, are used to increase survival in patients acutely exposed to myelosuppressive doses of radiation.

- Leukine, approved in 2018, Animal Rule ‘Yes’, increases survival in adult and pediatric patients (birth to 17 years) exposed to myelosuppressive radiation.

- Nplate, approved in 2021, Animal Rule ‘Yes’, increases survival in adults and pediatric patients (including term neonates) exposed to myelosuppressive radiation.

Decorporation agents promote the elimination of radioisotopes from the body. There are three therapeutics for decorporation of internalized radioisotopes that could result from a variety of scenarios, including an RDD. Prussian blue (Radiogardase™) is used to help decorporate internalized radioactive cesium and was approved in 2003¹³ (Table 1). The approval was based on human data (106 subjects) and dose-response and pharmacokinetic studies in animals.

Zinc-diethylenetriamine pentaacetate (Zn-DTPA) and Calcium-diethylenetriamine pentaacetate (Ca-DTPA) have similar label approvals as radio mitigating chelators indicated for treatment of individuals with known or suspected internal contamination with plutonium, americium, or curium to increase the rates of elimination.^{14, 15} Both were approved in 2004 based on clinical data that came from the treatment of individuals (286 patients) who were accidentally contaminated. Both chelators are considered equipotent when administered within 24 hours following internal contamination, but Zn-DTPA is considered less toxic and is therefore the recommended therapeutic for continued treatment (Table 1).

Nuclear Detonation—Considerations for Product Development

The NucDet scenario is probably the most complicated from both planning and response perspectives within the MCM development space. NucDets will cause infrastructure damage, resource limitations, and a large patient population with combined injuries, the degree of which being dependent on the nature of the incident (e.g., airburst vs. ground burst). Under such conditions, the first step will be triage of those who do not require immediate treatment, those requiring immediate treatment, and those who may be expectant mortalities. The biodosimetry programs at NIAID and BARDA are focused on developing biodosimetry devices that can use physiological readouts to help parse individuals in 2 phases along the continuum of care: (1) a point-of-care qualitative device that can rapidly identify individuals who received a significant dose of radiation from those who did not, in order to reduce the burden on the initial medical response, and (2) a high-throughput quantitative or semi-quantitative device to triage those needing immediate medical treatment into categories based on severity of damage. Although the FDA published a guidance on biodosimetry development in 2016,¹⁶ no biodosimetry device has been cleared by the FDA. Therefore, alternative medical assessments, including serial lymphocyte counts, vomiting, and clinical signs, are recommended as part of the federal response to a NucDet to estimate the radiation dose and initiate clinical management, although those readouts lack specificity and accuracy. Biodosimetry, based on biomarker expression changes that are both sensitive and specific to ionizing radiation exposure, would enable accurate estimation of the dose at the individual level. To date, however, no biomarker panel has demonstrated sufficient sensitivity and/or specificity to reach the desired performance and accuracy. Lack of biomarker concordance (dose response, time dependency, fold-change, homology) between animal models and humans, significant differences in expression levels between radiotherapy patients and the healthy population, and interindividual variability are major hurdles to overcome. Absence of suitable in vitro and in vivo surrogate models that could be used for validation studies to assess performance, safety, and efficacy of the tests has significantly hampered progress toward regulatory approval. Biodosimetry tools are urgently needed to refine initial estimation and provide better indications of radiation exposure to guide early- and late-stage medical management.

Polypharmacy

The complexity of NucDet injuries will require that we have multiple MCMs to treat the life-threatening sequelae and pathophysiologies that result from radiation, burn, and trauma. Similar to the biodosimetry program, we also need easily deployable treatments that can be used at the point-of-care, as well as definitive and comprehensive care solutions to align to the complexity of the NucDet response (see Coleman et al., for the description of the phased medical response for NucDetReference Coleman¹⁷). From a concept of operations perspective, performance of all MCMs must be considered in the context of a polypharmacy treatment protocol. Additional studies may be required to support regulatory approval to ensure products maintain efficacy and don’t result in unfavorable drug-drug interactions. However, it should be emphasized that in an emergency mass casualty incident, the standard of care and certain treatments and supplies that are typically available in health care settings likely will not be available at point-of-care or intermediate treatment stations.

Repurposing/Label Expansion

In initial preparedness discussions, the concept of repurposing commercial products and obtaining label expansion for contingent/MCM use was introduced. The myeloid cytokines and potentially other products in the oncology arena were recognized early on as products that could potentially be adapted for MCM use in the treatment of hematopoietic-acute radiation syndrome (H-ARS). Repurposing for an MCM indication has important potential advantages over developing a product de novo and solely as an MCM; as the approval pathway for the MCM indication can leverage existing approval safety and efficacy data from related commercial indications, thereby making the approval more reliant on human data and less reliant on surrogate animal data. Furthermore, a repurposed drug has a commercial market that can be leveraged for alternative stockpiling models (e.g., vendor managed inventories [VMIs]).Reference Homer, Raulli and DiCarlo-Cohen^18–Reference DiCarlo, Homer and Coleman²⁰ Additionally, repurposed products are products already in use by the health care community and therefore, health care providers are familiar with them and their use, which will be critical for any large-scale mass casualty incident. Repurposing is a key strategy for USG MCM development portfolios including NIAID and BARDA. Radiation, trauma, burn, and chemical injuries have pathophysiological similarities that could be leveraged for understanding the natural history of damage, identifying crucial targets for MCM intervention and, consequently, developing the same MCMs as treatment for multiple injuries.

FDA Animal Rule

For MCM approvals where human clinical trials are either unethical or not feasible, FDA developed and issued a finalized Animal Rule regulation in 2002, which requires relevant animal data in the context of conditions that approximate the threat causing injury.^{21, 22} To date, there have been 17 approvals for MCMs under the Animal Rule, including 4 within the Rad/Nuc arena^23–26 (Table 1).

The elements of the Animal Rule^{21, 22} state FDA will rely on animal studies to provide substantial evidence of effectiveness ONLY when:

• • There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product.

• • The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans.

• • The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity.

  • ○ There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product.

  • ○ The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans.

  • ○ The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity.

Myeloid Cytokines

Myeloid cytokines are the only Rad/Nuc MCMs that have been approved under the Animal Rule. As noted above, in another article in this issue (“Advanced Medical Countermeasures and Devices for Use During a Radiological or Nuclear Emergency”Reference DiCarlo²⁷) and elsewhere,Reference Cassatt, DiCarlo and Molinar-Inglis²⁸ the earliest effort in the development of MCMs against acute radiation syndrome (ARS) was to expand the label for licensed leukocyte growth factors using the Animal Rule pathway. This began in 2004 with a collaboration between NIAID, the FDA Office of Counterterrorism and Emergency Coordination (OCTEC), and Amgen (manufacturer of the two granulocyte colony-stimulating factor (G-CSF) drugs filgrastim (Neupogen®)²³ and pegfilgrastim (Neulasta®)²⁴). Based on the prior interactions with the FDA, pre-IND meeting requests were directed to the Division of Biological Oncology Products (DBOP) within the Center for Drug Evaluation and Research (CDER) beginning in 2004. FDA encouraged frequent meetings to discuss what would be needed in the supplementary Biological License Application (sBLA) submission. Discussions clarified the need to perform adequate and well-controlled studies in 2 animal species with mortality as a primary endpoint, to include secondary endpoints addressing the mechanisms of injury and its recovery.

To these ends, in 2005 NIAID, with later support from BARDA, awarded a Product Development Support (PDS) contract to the University of Maryland School of Medicine (UMSOM). Under this contract, facilities at the UMSOM and Indiana University School of Medicine were brought up to Good Laboratory Practice (GLP) standards and mouse and non-human primate (NHP) models were developed and/or refined. In 2007, Amgen ceased its collaboration with NIAID, but studies that supported NHP model developmentReference Farese, Cohen and Katz²⁹ and successful efficacy testing of Neupogen®Reference Farese, Cohen and Katz³⁰ were performed, and complete NHP study reports, along with supporting data from mouse studies,Reference Plett, Sampson and Chua³¹ were submitted to the FDA in 2010. These submissions set several activities into motion: First, to ensure consistency, all CDER reviews of RadNuc MCMs were assigned to the Division of Drug Imaging Products (DMIP), now the Division of Imaging and Radiation Medicine (DIRM). Second, additional data were required from the UMSOM for analysis, and the FDA conducted an inspection of the UMSOM, where the NHP studies were performed. Third, BARDA issued a Request for Proposal (RFP) for studies required under the Animal Rule and potential procurement of licensed growth factors that were shown to accelerate neutrophil recovery. Lastly, the FDA convened a joint meeting of the Medical Imaging Drugs Advisory Committee (AdComm) and the Oncologic Drugs AdComm on May 3, 2013, to discuss the safety and efficacy of approved leukocyte growth factors and their potential for approval under the Animal Rule.³² At the AdComm meeting, panelists discussed mechanisms of injury and repair, endpoints, MCM dose selection, and voted (17-1) that filgrastim was likely to produce clinical benefits following a Rad/Nuc incident. This meeting clarified the pathway for the approvals of G-CSF (Neupogen® and Neulasta® in 2015) and granulocyte-macrophage colony-stimulating factor (GM-CSF; Leukine® in 2018)²⁶ and eventual USG procurement of these MCMs. Recently, several biosimilars have been able to obtain regulatory label expansions as MCMs due to these efforts.

Interagency collaboration has been a key factor in regulatory progress for MCMs. FDA is solely responsible for formulating the regulations and policies, but the interagency interactions provided important feedback for FDA to refine and update the regulatory guidance, which, in turn, allowed NIAID and BARDA to move forward with the development. Besides the FDA meetings with sponsors, NIAID and BARDA have held discussions and informational meetings through DMIP/DIRM and OCTEC (now Counterterrorism and Emergency Coordination Staff, CTECS) and have co-sponsored workshops on radiation-induced lung,Reference Cassatt, Gorovets and Karimi-Shah³³ cutaneous,Reference DiCarlo, Bandremer and Hollingsworth³⁴ and gastrointestinalReference Winters, Marzella and Molinar-Inglis³⁵ injury. These meetings have helped to provide direction to NIAID and BARDA so that they, in turn, provide some level of clarification to partner organizations, both grantees and contractors, and their own model development efforts. These interactions, formal and informal, have also contributed to the development and updating of the FDA Guidances on the Animal Rule. These experiences also facilitated the 2021 FDA approval of the thrombopoietin receptor agonist, Nplate® (romiplostim, Amgen),²⁵ that resulted from a collaboration initiated between NIAID and Amgen in 2015 (efficacy, PK, and PD studies),Reference Bunin, Bakke and Green^36–Reference Bunin, Javitz and Gahagen³⁸ and culminated with regulatory support from a contract with BARDA.

Cell-Based Therapies

Bone marrow transplant (BMT) is anticipated to be a treatment option if a patient is refractory to cytokine therapy after acute exposure to ionizing radiation. BMT does not require FDA premarket review as it is covered by 42 CFR 121-Organ Procurement and Transplantation and is described in 21 CFR 1271.10(a) for Human cells, Tissues, or Cellular or Tissue-based Products (HCT/Ps).³⁹ To date, there are no data to clearly demonstrate the benefit of BMT in treating ARS, but the success within the oncologic community drives its consideration for use in a NucDet.

Next-generation cellular therapies that do not fall under HCT/Ps will have to be developed under the Animal Rule for an MCM indication. Several are in early development and have shown promise in preliminary studies. Challenges that need to be overcome include identifying the mechanism(s) of action (MOA) and developing potency assays that reflect those MOAs. Product developers should also consider that cellular therapies may require developing species-specific products for their respective animal models under the Animal Rule, which in turn would necessitate demonstration of comparability in function between animal and human products.

Burn and Blast MCM Products

The background for the development strategy for MCMs under the Burn and Blast (B/B) program has been described in the article by DiCarlo et al.Reference DiCarlo²⁷ The product development strategy necessitated the regulatory path for FDA approval for different products to follow specific requirements based on their indicated MOA in the management of B/B injuries. The program emphasizes and prioritizes potentially re-purposeable products, including products that can have shared indications across threat injuries.

Given the complexity of delivering care for burns and trauma across the care continuum, several MCMs are under development for various treatment targets. These address healthcare gaps and/or provide substantial efficiency in delivery of care.Reference Gill⁴⁰ Since 2013, the BARDA B/B program has developed a range of MCMs for burns and blast trauma. Fundamental requirements necessitate engagements between the developer and the FDA as early and as often as feasible at critical milestones. Additional strategies included exploring the FDA’s Breakthrough Device Designation Program,⁴¹ which offers engagement opportunities. Under the B/B program, 5 different MCM development projects have successfully obtained Breakthrough Designation as a strategy for receiving ongoing feedback from the FDA. Active engagement with the FDA has enabled us to craft smarter strategies as outlined below.

Regulatory Strategies for Artificial Intelligence (AI) in MCMs

With the introduction of AI-based algorithms, which can enhance the functionality of many approved MCMs, established devices are likely to be reevaluated based on their new capability and the changes to the risk profile. The FDA has created new guidance documents in the AI space.Reference Food and Administration⁴² These provide basic tenets on the role of the AI software/algorithm. The FDA has provided guidance on how to interpret results from diagnostic tests that, in turn, determines the impact of the risks from false positive and false negative results on the delivery of patient care. It is critical that product functionality is established. It is also important to determine where in the delivery of care the AI functionality renders the decision for consideration by the physician. This incorporates the decision-making role of the device in a clinical setting and the user interactions. Table 2 is a summary of a few regulations and their nuances, which increase the regulatory complexity—all of which is best discussed with the FDA via interactive meetings. It is critical and incumbent on the sponsor to ensure the FDA understands the product use case of the AI-enhancement in delivery of care compared to the current standard of care.

Table 2.

Regulations in image processing through computer-aided detection and diagnosis(CADe/x)

Table 2. Long description

The table consists of four columns and four main data rows.

Row 1: Regulation 21 C F R 892.2050. Device type: Medical Image Management and Processing System. Definition: Devices for review and digital processing of medical images used for disease detection, diagnosis, and patient management. Capabilities: Advanced image manipulation functions like segmentation, multimodality registration, and 3 D visualization; complex quantitative analysis including semi-automated and time-series measurements.

Row 2: Regulation 21 C F R 892.2060. Device type: Radiological computer-assisted diagnostic C A D x software for Lesions suspicious of cancer. Definition: Image processing prescription device that aids in characterization of lesions suspicious for cancer. Capabilities: Analyzes acquired medical images such as M R I, mammography, radiography, and C T; provides detailed information to clinicians for diagnosis and management decisions.

Row 3: Regulation 21 C F R 892.2070. Device type: Medical image analyzer. Definition: Detect and highlight potential abnormalities in medical imaging, including computer-assisted or aided detection C A D e devices for applications like mammography and lung nodules. Capabilities: Incorporate pattern recognition and data analysis; operates on previously acquired images; complements but does not replace radiologist review; not intended for triage or to recommend diagnosis.

Row 4: Regulation 21 C F R 892.2080. Device type: Radiological computer-aided triage and notification C A D t software. Definition: Prioritizes radiological images based on computer-aided image analysis and notifies clinicians about time-sensitive images. Capabilities: Utilizes computer-aided image analysis; does not mark or highlight specific locations in original images; does not remove cases from reading queue; operates parallel to standard of care.

Animal Models, FDA Feedback and Other MCMs

ARS is a systemic, whole-body injury that affects all organ systems. We have learned over time that we do not understand the natural history of lethal radiation injury as well as we should. For many products under development for ARS under the Animal Rule during the past two decades, there was one overwhelming piece of feedback from the FDA: we do not understand a product’s MOA well enough or how a product’s MOA relates to radiation injury. We are gradually making progress in understanding the underlying pathophysiology in the various described subsyndromes (i.e., hematopoietic, gastrointestinal, cutaneous, etc.), and in the development of new animal models and new platform technologies like microphysiological systems. Product development under the Animal Rule is an iterative process between developers and regulators, and as additional information is gained, additional models and products can be evaluated.

Even with repurposing, there will be information gaps including efficacy, bridging between models and humans, drug supply, drug product owner interest, and intellectual property considerations.

Animal model development does not have an obvious path for all products. There are products that have very stringent species specificity that have resulted in significant regulatory hurdles through the Animal Rule pathway, despite these products being licensed commercial products for relevant etiologies, like thrombocytopenia. This begs the question: Are there circumstances where human clinical data might suffice when combined with limited animal data? For the above instance, for a commercial drug with a well-characterized mechanism of action that is being repurposed for a radiation MCM indication, where that same mechanism of action is behind the therapeutic effect, should a powered pivotal study still be required (e.g., under the Animal Rule)?

Another challenge in evaluating and choosing models is lifespan. In humans, delayed effects of acute radiation exposure (DEARE) can take months to years to develop, but only days to months in animals. It is unclear if the compressed timeframe in animals is of sufficient duration to accurately reflect the natural history of radiation exposure in humans. An additional challenge is the question of the dose of radiation required to see the effects. In most cases, the dose to animals is well above the LD₅₀, requiring special measures, such as bone marrow sparing, to keep an adequate study population alive long enough to test the study drug.Reference Williams, Jackson and Shah^43–Reference MacVittie, Farese and Parker⁴⁶

Nonetheless, advancements in our understanding of the natural history of radiation injury have informed iterative changes to the models previously used for the myeloid cytokine pivotal studies and approval. For instance, the role of endothelial/vascular damage and potential role of blood products as MCMs is clearer now than when the first pivotal models were designedReference Satyamitra, DiCarlo and Taliaferro⁴⁷ and, consequently, the pivotal models utilized for Leukine® and the thrombocytopenic therapies excluded blood product transfusion as supportive care.Reference Bunin, Bakke and Green^36, Reference Clayton, Khan-Malek and Dangler⁴⁸ However, no comprehensive studies examining the potential efficacy of blood products for treating acute radiation syndrome have been done. Additionally, although traditionally viewed as a supportive care element, broad-spectrum antibiotics are now recognized as MCMs,Reference Phipps, Bergmann and Albrecht⁴⁹ and the models have shifted from empiric use to prophylactic use. For studies under the Animal Rule, considerations of what to include as “supportive care” should weigh what may or may not be available for use in a mass casualty incident and how inclusion of that element may impact evaluation of efficacy. For many more recent studies, “limited” supportive care has been adopted.Reference Clayton, Khan-Malek and Dangler^48, Reference Basile, Ellefson and Gluzman-Poltorak^50, Reference Doyle-Eisele, Brower and Aiello⁵¹

Looking Forward

The RadNuc MCM space is unquestionably complicated and full of challenges. Over the span of forty-plus years since the approval of KI tablets, the approach and strategy for how to approve products that will hopefully never be used has changed considerably. There has been a shift from the primary reliance on human pharmacodynamics data from similar conditions, supplemented by animal data, to the implementation of the Animal Rule and the primary reliance on animal efficacy data, with human safety and other data being supportive. During this evolution, we have seen some successes and failures. Ultimately, how we think about planning for extreme emergency situations needs to be revisited again and again.

What has been our return on investment under the Animal Rule over the past 20 years since its implementation? Are there additional or other regulatory strategies to assess the risk and benefit of a potential emergency use of a product that are more cost effective and require less animal testing while maintaining an understanding of safety and efficacy? What regulatory pathways for MCM development might be used? Should it depend on the indication? What can be done in the circumstance where there are no FDA-accepted animal models of human disease? These questions and others should be explored more thoroughly to ensure we are maximizing our efforts in the most expedient and efficient way possible to ensure we are prepared to protect victims of Rad/Nuc incidents.