Groups suggest tweaks to FDA’s guidance on developing drugs to treat radiation exposure
Stakeholders urged the US Food and Drug Administration (FDA) to broaden the scope of its guidance on developing drugs for acute radiation syndrome (ARS) to treat downstream exposure, while one group wants the guidance to more fully address developing these drugs for prophylactic uses.The comments were made in response to FDA’s call for feedback on a draft guidance released in April. (RELATED: FDA draft guidance aims to help sponsors develop drugs for radiation exposure, Regulatory Focus 19 April 2023)
ARS applies to a variety of clinical indications resulting from high doses of exposure to radiation. The Centers for Disease Control and Prevention (CDC) defines ARS as “an acute illness caused by irradiation of the entire body (or most of the body) by a high dose of penetrating radiation in a very short period of time (usually a matter of 45 minutes).”
Guidance should address downstream exposure
FDA states that the draft guidance is not intended for treating the “downstream effect” of exposure such as sepsis and does not address devalued effects of acute radiation exposure, such as radiation-induced lung injury.
Both the American Academy of Clinical Toxicology (AACT) and the Biomedical Advanced Research and Development Authority (BARDA) requested that the scope of the guidance be expanded to address the downstream effects of radiation.
AACT wrote that “after the initial ionizing radiation insult, many effects of interest may be considered downstream and a direct or indirect effect of the radiation exposure. While the intent may not be to evaluate new antibiotics for sepsis, for example, preventing sepsis or an inflammatory cascade via a particular intervention may fall under ‘downstream’ effect based on the current definition.”
BARDA questioned “why are downstream effects not considered? For example, antibiotics are as effective as myeloid cytokines in improving survival but could be considered to be treating a downstream effect.” BARDA was created to develop medical countermeasures for viral threats with pandemic potential.
Along similar lines, the National Strategic Research Institute (NSRI) complained that the document does not adequately developing these drugs for prophylactic uses.
The guidance only makes a brief reference to such uses, stating that “design considerations for animal efficacy studies would be different for a drug for prophylaxis compared with a drug for treatment. Pre-exposure prophylaxis studies should be designed to determine the likely time course of the prophylactic effect (i.e., the minimum time the subject must wait after taking the drug before radiation exposure) and how long the prophylactic effect lasts.”
The group suggested adding text similar to FDA’s 2019 guidance for industry on Influenza: Developing Drugs for Treatment and/or Prophylaxis. The text states that “prophylaxis and treatment trials should include sufficiently long follow-up to detect symptom recurrence after temporary improvement, late adverse events, etc.”
Animal models
In other areas, BARDA requests more information on using animal models where data is incomplete in humans.
BARDA wrote that “effects other than bone marrow suppression are not well understood in humans, given the limited available data. Animal models that adequately reflect the radiation-induced injury in humans to address the requirements of the Animal Rule, other than for H-ARS, [Hematopoietic Acute Radiation Syndrome] may not be available. The guidance is silent on recommendations for how to select animal models under such conditions and provides only a summary of the logic that FDA used for a specific set of products (bone marrow growth factor/cytokines), that may not easily translate to classes of products addressing other radiation-induced pathophysiologies.”
FDA notes that treatments for ARS will generally be approved under the Animal Rule, which enables the approval of drugs or biologics without human clinical trials when such studies are not ethical or feasible.
BARDA also suggested that FDA hold a workshop to discuss the development of ARS medical countermeasures (MCMs) and the Animal Rule.
Comments
