Most asked nonclinical questions from regulatory authorities
Safety issues are the main themes for nonclinical requests from regulatory authorities. Although you are submitting an almost complete IND package or CTD for NDA, nonclinical experts on the other side of the desk will ask you to add supplementary information or whole bridging studies.
The major areas of concerns are focused on:
Repeated dose studies: histological findings may show structural changes of liver, GI tract, bone marrow, reproductive organs, etc. Expert analysis to take into account degree and extension of changes, reversibility, species differences, toxicokinetics, NOEL, NOAEL and available human data
Immunotoxicity: very important topic, often coming from suspect findings in repeated dose studies. Haematology changes as well as reduced spleen/thymus weights may indicate a possible effect on the immune system. Review data reported, species differences and, if the case, run special studies.
Reproductive studies: very few drugs can show absolute lack of the effects when given to pregnant animals. Maternal toxicity and occasional findings in the newborns may contribute to classify the drug in category C (FDA>Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks). Expert analysis to consider colony data, dosing, NOAEL, placental transfer.
Impurities: hot topic with genotoxicity and impurities content of the batches. Expert analysis to consider history of synthetic changes and efforts to reduce impurities levels up to “acceptable” amount, and final exposure of patient population
Cardiovascular safety pharmacology: here the set of in vitro/in vivo studies may come to contrasting results. Human experience (if any) and considerations about systemic exposure from PK animal / PK (expected) human are of relevant value.Most asked nonclinical questions from regulatory authorities