Strategies That Enable Successful FIH and Beyond | An ISSX 2023 Short Course

Recorded On: 09/10/2023

Overview
Contents (4)

This short course, featured at the 25th North American ISSX Meeting in September 2023, is aimed at scientists desiring to gain experience in successful IND submissions that enable first-in-human (FIH) studies with clear line of sight to successful approvals. The course is broken into three parts with three experienced lecturers across industry and FDA. The first section covers translational aspects, modeling approaches, and FIH exposure/dose predictions in the context of the desired therapeutic benefit. The next section focuses on the work needed in the preclinical toxicology package (e.g. expected mechanism-based toxicity, off-target toxicity, species selection, target exposure/dose justifications and metabolites). The last section focuses on understanding the absorption, distribution, metabolism, and excretion (ADME) of the investigational drug with a particular emphasis on drug-drug interactions and inclusion/exclusion criteria in the initial FIH studies and the long range view towards drug approval.

A Successful Preclinical Toxicology Package
Shaji Theodore, US Food and Drug Administration, Silver Spring, Maryland, USA

ADME considerations from FIH to Drug Approval
Rosa Sanchez, Merck, West Point, Pennsylvania, USA

Pharmacology and Translational Aspects
Mirjam Trame, Certara, Boston, Massachusetts, USA

Chairs: Christine Fandozzi, J&J, Springhouse, Pennsylvania, USA and Rosa Sanchez, Merck, West Point, Pennsylvania, USA

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SC3.1 Adme Considerations From FIH To Drug Approval | Rosa Sanchez

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SC3.2 Pharmacology and Translational Aspects | Mirjam Trame

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SC3.3 A Successful Preclinical Toxicology Package|Shaji Theodore

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Open to view video. The first-in-human (FIH) clinical trial is a critical first step in the transition of a drug or biologic from the discovery stage to clinical development and eventually to a human therapeutic product. Lack of prior human exposure and consequent lack of human safety information necessitates reliance on nonclinical safety information that must be submitted with the investigational new drug application (IND) to enable FIH studies. Typical nonclinical package for FIH studies include in vitro primary pharmacology, proof-of concept in relevant animal model/s, secondary pharmacology to assess off-target activity, safety pharmacology studies of vital organ systems primarily respiratory, cardiovascular, and central nervous systems, pharmacokinetics, toxicokinetics, genotoxicity, and general toxicology studies. Since safety of the trial subjects is of utmost importance, a successful preclinical toxicology submission to support an FIH trial should include characterization of target organ toxicity, reversibility of adverse effects, dose dependence, and relationship to systemic exposure. Nonclinical safety information from well-designed preclinical studies aid in the estimation of an initial safe starting dose and a safe dose range for the human trials and help predict potential adverse effects that could occur under the conditions of the clinical trial so that those safety parameters could be monitored in the clinic. The no observed adverse effect level (NOAEL) derived from pivotal toxicology studies in the most relevant species conducted in accordance with good laboratory practice generally serves as the starting point for determining a reasonably safe starting dose, particularly for healthy volunteer studies, as well as the maximum dose that can be safely administered in the trial. Although the NOAEL is most commonly used to set start doses, other metrics such as minimally anticipated biologic effect level (MABEL), pharmacologically active dose (PAD) or highest non-severely toxic dose (HNSTD) can apply depending on the circumstance. Studies needed to obtain adequate nonclinical safety information to support FIH trial could vary depending on the type of therapeutic product, trial subjects, single or multiple dosing, and its intended use in the clinic. Specific considerations may apply to oncologic drugs, other severe life-limiting conditions and where the pediatric population is the primary target.

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Strategies That Enable Successful FIH and Beyond | An ISSX 2023 Short Course

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