Regulatory decision strategy for entry of a novel biologic therapeutic with a clinically unmonitorable toxicity into clinical trials: Pre-IND meetings and a case example

The following material was derived from a synthesis of case histories taken from investigational new drug (IND) applications and drug sponsors' experi ences, utilizing fictionalized data to avoid any resemblance to any proprie tary information; any such resemblance is accidental. These examples are us ed as an instructional scenario to illustrate appropriate handling of a dif ficult toxicology issue. In this scenario, a drug caused a toxicity in anim als that was detected only by histopathologic analysis; if it were to devel op in patients, no conventional clinical methods could be identified to mon itor for it. It is not unusual for a firm to cancel clinical development pl ans for a lead drug candidate that causes such a toxicity, especially if su ch a drug is intended for use as a chronic therapeutic in a population of p atients with a chronic disease. This case synthesis was inspired by a Food and Drug Administration (FDA) agreement to allow such a product to proceed into clinical trials after substantive pre-IND discussions and agreement on well-considered toxicology program designs. The scientists most closely in volved in the strategy development included the sponsor's toxicologist, vet erinary toxicologic pathologist, and pharmacokineticist, as well as the FDA 's reviewing pharmacologist. The basis of this decision was thorough toxici ty characterization (1-month studies in 2 species); correlating toxicities with a particular cumulative area under the curve (AUC) in both species; id entification of the most sensitive species (the species that showed the low er AUC correlating with toxicity); allometric assessment of clearance of th e drug in 3 nonhuman species; construction of a model of human kinetics (ba sed on extrapolation from animal kinetics); and finally, estimation of clin ical safety factors (ratios of the human estimated cumulative AUC at the pr oposed clinical doses, over the animal cumulative AUC that correlated with the no adverse effect levels). Industry and FDA scientists negotiated a joi nt assessment of risk and benefit in patients, resulting in the FDA permitt ing such a compound to enter into clinical trials for a serious autoimmune disease. Such constructive, early communication starts with the pre-IND mee ting, and the conduct and planning for this meeting can be very important i n establishing smooth scientific and regulatory groundwork for the future o f a drug under IND investigation.