Where are the medical countermeasures against the ARS and DEARE? A current topic relative to an animal model research platform, radiation exposure context, the acute and delayed effects of acute exposure, and the FDA animal rule

Abstract

Purpose

A question echoed by the National Biodefense Science Board (NBSB) in 2010, remains a reasonable question in 2023; ‘Where are the Countermeasures?’. A critical path for development of medical countermeasures (MCM) against acute, radiation-induced organ-specific injury within the acute radiation syndrome (ARS) and the delayed effects of acute radiation exposure (DEARE) requires the recognition of problems and solutions inherent in the path to FDA approval under the Animal Rule. Keep Rule number one in mind, It’s not easy.

Considerations

The current topic herein is focused on defining the nonhuman primate model(s) for efficient MCM development relative to consideration of prompt and delayed exposure in the context of the nuclear scenario. The rhesus macaque is a predictive model for human exposure of partial-body irradiation with marginal bone marrow sparing that allows definition of the multiple organ injury in the acute radiation syndrome (ARS) and the delayed effects of acute radiation exposure (DEARE). The continued definition of natural history is required to delineate an associative or causal interaction within the concurrent multi-organ injury characteristic of the ARS and DEARE. A more efficient development of organ specific MCM for both pre-exposure and post-exposure prophylaxis to include acute radiation-induced combined injury requires closing critical gaps in knowledge and urgent support to rectify the national shortage of nonhuman primates. The rhesus macaque is a validated, predictive model of the human response to prompt and delayed radiation exposure, medical management and MCM treatment. A rational approach to further development of the cynomolgus macaque as a comparable model is urgently required for continued development of MCM for FDA approval.

Conclusion

It is imperative to examine the key variables relative to animal model development and validation, The pharmacokinetics, pharmacodynamics and exposure profiles, of candidate MCM relative to route, administration schedule and optimal efficacy define the fully effective dose. The conduct of adequate and well-controlled pivotal efficacy studies as well as safety and toxicity studies support approval under the FDA Animal Rule and label definition for human use.

Keywords:

• The ARS and DEARE
• NHP models
• medical countermeasures
• nuclear exposure context

Acknowledgments

Thanks to my co-pilot, Ann M. Farese, Assistant Professor, Dept. Radiation Oncology, University of Maryland, School of Medicine and a supportive ‘village’ of colleagues and to Paul Blake, PhD, CHP, FHPS, Health Physicist/Portfolio Manager, Nuclear Test Personnel Review (RD-NTS), Defense Threat Reduction Agency for his personal communications.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research effort was supported by the following National Institutes of Allergy and Infectious Diseases (NIAID) contracts HHSN272201000046C and SRI/NIAID Contract HHSN272201500013I.

Notes on contributors

Thomas J. MacVittie

Thomas J. MacVittie, MS, PhD, is a Professor Emeritus in the Department of Radiation Oncology at the University of Maryland, School of Medicine. He has focused research on the effects of acute radiation exposure on the ARS and delayed effects of acute radiation exposure (DEARE) in nonhuman primate models and their treatment with supportive care and selected organ-specific drugs. The research team performed the pivotal studies for FDA approval of Neupogen and Neulasta under the FDA Animal Rule. The research team was focused on developing a more strategic approach to MCM development and the refinement of nonhuman primate animal models for the H-, GI-ARS, lung damage and multi-organ injury to include the heart and kidney. Always trying to as a better question.