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Medical Countermeasure Program

The division is home to one of the largest medical countermeasure (MCM) programs in the world. The division has the necessary technical capabilities, infrastructure, and resources to conduct preclinical efficacy screens in a range of small and large animal models against acute radiation sickness (ARS) and delayed effects of acute radiation exposure (DEARE). All studies are conducted in compliance with the U.S. Food and Drug Administration (FDA) Good Laboratory Practice (GLP) regulations. The division, through partnership with the National Institutes of Allergy and Infectious Disease/National Institutes of Health, the Biomedical Advanced Research and Development Authority (BARDA), industry, and academia has made significant advances in development of new pharmacotherapeutics and repurposing of existing therapies for use as MCMs.


Members


The MCM program is comprised of a powerful team of individuals with extensive and long-term experience with product development leading to FDA approval under the Animal Rule regulatory pathway. Models developed within the Medical Countermeasure Program are designed to satisfy the objectives of the FDA Animal Rule criteria (21 CFR § 314.610, drugs; § 601.91, biologics) for pivotal efficacy testing and product approval. The MCM team is highly experienced and capable in performing studies to further product development, including determining the best route of administration, dose, duration, timing, and therapeutic index.

The Division’s models of ARS/DEARE are thoroughly described in published literature and copies of relevant publications can be provided upon request. Preclinical studies control for all factors that may influence data interpretation and outcomes including dosimetry, strain differences, animal gender/age, supportive care, infection, stress, batch effects, and survival (a soft endpoint) through rigorous quality assurance/quality control and strict adherence to study protocols and intensive training of all staff and personnel assigned to studies.


Results-driven approach to Research and Development

Key deliverables over the past three years include but are not limited to the following:

  • Development and refinement of small and large animal models of ARS and DEARE, with quantitative endpoints, that are linked across syndromes and species;
  • Achieved concurrence of animal models of ARS and DEARE at Type B and C meetings as appropriate for candidate MCM screening in support of product approval through the U.S. Food and Drug Administration (FDA) Animal Rule (AR);
  • Generated the source data in a GLP-compliant preclinical trial leading to the first drug approvals by the FDA for the treatment of myelosuppression resulting from ARS;
  • Published >50 peer-reviewed research articles related to model development, MCMs, and mechanism of radiation damage in tissue with significant short and long-term impact to aid in defining the indication and treatment regimen for radiation countermeasures;

Capabilities within the MCM program include, but are not limited to the following:

  • Relevant existing small and large RadNuc models with established dose–response relationships and defined dose- and time-dependent incidence, severity, and latency of H-ARS, GI-ARS, DEARE-lung, cutaneous radiation injury (CRI) in the context of a nuclear terrorist event;
  • Established ARS/DEARE animal model research platform that addresses many of the critical knowledge gaps associated with successful adherence to FDA AR criteria required for product licensure or EUA considerations;
  • Collaboration with imaging/biomarker team led by Dr. Maureen Kane in the UMB School of Pharmacy focused on molecular analysis and tissue imaging using matrix-assisted laser desorption ionization (MALDI) and imaging mass spectrometry (IMS) that is linked to cellular analysis and biomarker discovery (genomic, proteomics, metabolomics);
  • Capability to link molecular and cellular analysis to animal signs that reflect morbidity and mortality along the time course of organ-specific dysfunction and recovery;
  • Sophisticated noninvasive endpoints for evaluating pathogenesis of injury, including respiratory function, MR/SPECT/PET/CT imaging and ultrasound/echocardiography;
  • Incorporation of quantitative pharmacology in trial design and data analysis through collaboration with Dr. Joga Gobbaru, Director, Center for Translational Medicine;
  • All studies comply with the USDA Animal Welfare Act, 9 Code of Federal Regulations, Parts 1,2, and 3; the Guide for the Care and Use of Animals, National Research Council, National Academic Press, Washington, D.C., 1996, and UMSOM Institutional Animal Care and Use Policies; and
  • All GLP studies comply with 21CFR, Part 58, Good Laboratory Practices for Nonclinical studies for FDA.

Data Quality and Transparency

The Division adheres to a quality plan that complies with the U.S. Food and Drug Administration Good Laboratory Practice regulations and industry-standards for preclinical contract research. To ensure adequate design, conduct, and reporting of MCM studies, the division has a programmatic management team of administrators, quality assurance and regulatory personnel, and data and document management groups to oversee, manage, and track contract objectives and deliverables, allowing us to keep our efforts on budget, within scope, and on schedule. Research is conducted in a purpose-built research facility dedicated to MCM screening that is fully equipped with state-of-the-art equipment and animal housing plus office space for research staff, administration, and regulatory personnel.

The MCM program utilizes an adaptive trial design to minimize the total number of animals required for estimation of the dose-modifying effects of candidate MCMs on major morbidity/mortality. Through collaborations with investigators within the University of Maryland School of Pharmacy, the division conducts animal toxicology and safety studies and performs pharmacokinetic/pharmacodynamic modeling and simulation design. The program is supported by four full-time board-certified medical physicists as well as additional support from dedicated dosimetrists. Further details are available under Contract Research Services.


Selected publications related to ARS/DEARE in animal models

  1. Jackson IL, Vujaskovic Z, Down J. Revisiting strain-related differences in radiation sensitivity of the mouse lung: recognizing and avoiding the confounding effects of pleural effusions. Radiat Res 2010;173:10–20. PMCID: PMC2818983.
  2. Jackson IL, Vujaskovic Z, Down JD. A further comparison of pathologies following thoracic irradiation among different mouse strains: finding the best preclinical model for evaluating therapies directed against radiation induced lung damage. Radiat Res 2011;175:510–518. PMCID: PMC3110676.
  3. Jackson IL, Xu P, Hadley C, Katz BP, McGurk R, Down JD, Vujaskovic Z. A preclinical rodent model of radiation-induced lung injury for medical countermeasure screening in accordance with the FDA animal rule. Health Phys 2012;103:463–473. PMCID: PMC3604892.
  4. Jackson IL, Xu PX, Nguyen G, Down JD, Johnson CS, Katz BP, Hadley C, Vujaskovic Z. Characterization of the dose response relationship for lung injury following acute radiation exposure in three well established murine strains: developing an interspecies bridge to link animal models with human lung. Health Phys. 2014;106(1):48-55. PMID: 24276549.
  5. Shea-Donohue, T., Fasano, A., Zhao, A., Notari, L., Yan, S., Sun, R., Bohl, J. A., Desai, N., Tudor, G., Morimoto, M. et al. (2016). Mechanisms Involved in the Development of the Chronic Gastrointestinal Syndrome in Nonhuman Primates after Total-Body Irradiation with Bone Marrow Shielding. Radiation Research 185, 591-603.
  6. Cui, W., Bennett, A. W., Zhang, P., Barrow, K. R., Kearney, S. R., Hankey, K. G., Taylor-Howell, C., Gibbs, A. M., Smith, C. P. and MacVittie, T. J. (2016). A non-human primate model of radiation-induced cachexia. Sci Rep 6, 23612.
  7. Dorr, H., Lamkowski, A., Graessle, D. H., Bennett, A., Shapiro, A., Farese, A. M., Garofalo, M., MacVittie, T. J. and Meineke, V. (2014). Linking the human response to unplanned radiation and treatment to the nonhuman primate response to controlled radiation and treatment. Health Phys 106, 129-34.
  8. Farese, A. M., Brown, C. R., Smith, C. P., Gibbs, A. M., Katz, B. P., Johnson, C. S., Prado, K. L. and MacVittie, T. J. (2014). The ability of filgrastim to mitigate mortality following LD50/60 total-body irradiation is administration time-dependent. Health Phys 106, 39-47.
  9. Farese, A. M., Cohen, M. V., Katz, B. P., Smith, C. P., Gibbs, A., Cohen, D. M. and MacVittie, T. J. (2013). Filgrastim improves survival in lethally irradiated nonhuman primates. Radiation Research 179, 89-100.
  10. Farese, A. M., Cohen, M. V., Katz, B. P., Smith, C. P., Jackson, W., 3rd, Cohen, D. M. and MacVittie, T. J. (2012). A nonhuman primate model of the hematopoietic acute radiation syndrome plus medical management. Health Phys 103, 367-82.
  11. Farese, A. M., Cohen, M. V., Stead, R. B., Jackson, W., 3rd and Macvittie, T. J. (2012). Pegfilgrastim administered in an abbreviated schedule, significantly improved neutrophil recovery after high-dose radiation-induced myelosuppression in rhesus macaques. Radiation Research 178, 403-13.
  12. Garofalo, M., Bennett, A., Farese, A. M., Ward, A., Taylor-Howell, C., Cui, W., Gibbs, A., Lasio, G., Jackson, W., 3rd and MacVittie, T. J. (2014). The delayed pulmonary syndrome following acute high-dose irradiation: a rhesus macaque model. Health Phys 106, 56-72.
  13. Prado, C., Kazi, A., Bennett, A., MacVittie, T. and Prado, K. (2015). Mean Organ Doses Resulting From Non-Human Primate Whole Thorax Lung Irradiation Prescribed to Mid-Line Tissue. Health Phys 109, 367-73.