Chapter 8 – Preparation of a Preclinical Dossier to Support an Investigational New Drug (IND) Application and First-In-Human Clinical Trial

The submission of an Investigational New Drug (IND) application is the culmination of years of research on the part of chemists, nonclinical scientists, regulatory personnel, and clinicians. Not only have they produced an appropriate drug candidate to warrant testing in humans, they have, as a team, integrated their data into a cohesive argument that supports the safe dosing of human subjects, be they healthy volunteers or patients. The toxicologist is an essential participant of the team, as he or she will be responsible for coordinating the conduct of the toxicology studies and the writing of the toxicology sections of the regulatory submission; when limited by company personnel, the toxicologist may also be tasked with developing the pharmacology and pharmacokinetic sections. The core nonclinical component of the IND is the Nonclinical Overview (NCO), which, in conjunction with other summary documents and the study reports in the Common Technical Document (CTD), profiles the biological activity, disposition, and toxicology of the drug candidate. In addition, the toxicologist is intimately involved with the derivation of the clinical starting dose based on the no-observed-adverse-effect-levels (NOAELs) determined from the most sensitive species tested, and/or on the minimally active pharmacologic dose. This chapter provides an overview of the nonclinical sections of an IND, with suggestions on content and with particular emphasis on the toxicologist's role.