Development and Licensure of Medical Countermeasures for Platelet Regeneration after Radiation Exposure

The Department of Health and Human Services (HHS) is charged with protecting civilian populations by providing leadership in research, development, acquisition, deployment and use of effective medical countermeasures (MCMs) for treatment of injuries resulting from a radiological/nuclear incident. HHS has assigned the National Institute of Allergy and Infectious Diseases (NIAID) to develop and implement a research and development agenda (1). After unintentional radiation exposure in the hematopoietic dose range (,2 Gy to 8 Gy), potentially life-threatening neutropenia and thrombocytopenia can result, increasing the risk of death due to opportunistic infections and/ or hemorrhage (2). Although both conditions are likely to be major contributors to mortality in untreated individuals, little recent work had been done to develop drugs to enhance platelet counts after irradiation, and there are currently no licensed therapeutics (other than blood products) in the Strategic National Stockpile for treatment of this radiation-induced complication. To address this aspect of radiation damage, NIAID funded a portfolio of grants in late 2008 to develop MCMs to mitigate/treat radiation-induced thrombocytopenia and enhance survival. Supported research includes studies designed to generate data that would be required by the U.S. Food and Drug Administration (FDA) for licensure of an MCM as a mitigator of radiation-induced thrombocytopenia (RIT). The NIAID Radiation Countermeasures Program held a workshop on March 22–23, 2010 to bring together representatives from U.S. Government (USG) agencies with researchers who are developing MCMs and animal models to evaluate approaches to enhance regeneration of platelets after radiation exposure [(3); available online at http://dx.doi. org/10.1667/ RROL01.1]. The main goal of the discussion session that followed the science presentations was to clarify issues regarding potential paths forward for FDA licensure of products for a hematopoietic, acute radiation syndrome (ARS) indication and encourage discussion about the challenges involved in development of NIAID-funded (and other) MCMs to minimize thrombocytopenia and enhance survival after unintentional radiation exposure. After irradiation, megakaryocytes, which give rise to platelets, migrate to the osteoblastic niche (4). Megakaryocytes in the circulation are known to be more radioresistant to radiation than other bone marrowderived cells; however, their progenitor populations appear to be more radiosensitive (5). Depending on the degree of radiation damage, a drop in platelet count can be observed in less than a week (6), with the risk of life-threatening bleeding increased as the level of circulating platelets drops below 20,000/mm. In small accidents, supportive transfusion will be part of medical management; however, logistical requirements to provide care to large numbers of victims after a mass casualty incident are great, and emergency preparedness experts believe that an effective pharmacological therapy that mitigates or treats radiation-induced thrombocytopenia would offer dramatic advantages. Thus preferred drugs are those that can be easily administered (e.g. oral, subcutaneous, intramuscular routes of delivery) with low toxicity. Although some drugs are currently in development to treat RIT after cancer radiotherapy, they are often administered as radioprotectors – in advance of the radiation exposure. Due to the challenges involved in providing MCMs in the wake of a mass casualty incident, treatments are not expected to be available until least 24 h after an event, so drugs that are effective at this time postexposure (and beyond) are the most desirable.