Drugs

Guide on Nonclinical Immunotoxic Evaluations

FDA has released a final guidance entitled “Nonclinical Evaluation of the Immunotoxic Potential of Pharmaceuticals.” The document is intended to assist sponsors in such evaluations of unintended immunosuppression or stimulation (including hypersensitivity), which can include adverse effects of exaggerated pharmacology of pharmaceuticals that are intended to act as immunomodulators.

The guidance notes that International Council on Harmonization documents ICH S8 and ICH S6(R1) also cover nonclinical immunotoxicity assessments of small molecule drugs and biopharmaceuticals is provided by ICH S8 and ICH S6(R1). “The following concepts for the assessment of immunosuppression risk should be considered in conjunction with these guidances,” it says. “For pharmaceuticals (including biopharmaceuticals) that are intended to act via a suppressive immunomodulatory mechanism of action (MoA), sponsors should fully assess the known immunobiology of the intended mode of action as it relates to the potential for adverse consequences of exaggerated pharmacology. For less well-characterized immune targets, this assessment may warrant one or more dedicated nonclinical studies to better inform the risk of exaggerated target engagement.”

Additionally, the guidance says dedicated assays may be warranted to characterize the effects of the pharmaceutical on other related immune functions. “The specifics of on- and off-target assay selection should be dictated by the intended MoA of the pharmaceutical along with scientific evaluation of how the intended immune suppression may affect related activities of the immune system,” it explains.

If a biopharmaceutical is not intended to affect the immune system, sponsors can consider performing an integrated evaluation of the potential for unintended immunosuppression, according to the agency. “This evaluation could be similar in principle to the weight-of-evidence (WoE) evaluation as described in ICH S8,” it says. “Whether any additional studies are warranted would be guided by the findings of the integrated evaluation. For small molecule drugs that act via an antiproliferative MoA, such as those used to treat cancer, follow-up assays such as those discussed in ICH S8 are generally not warranted.”

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