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
Key:
Complete
Next
Failed
Available
Locked
SC3.1 Adme Considerations From FIH To Drug Approval | Rosa Sanchez
Open to view video.
Open to view video.
First in human submissions such as INDs and IMPDs typically include information on the absorption, distribution, metabolism, excretion and assessment of drug interaction risk for a drug candidate. All in the context of projected efficacious human exposures, dosing regimen, route of administration and treatment duration. As a drug candidate proceeds through clinical development and reaches the stage of a marketing application, the nonclinical package expands as clinical experience builds. In preparation for filing, a narrative that integrates nonclinical and clinical data develops and is detailed in the common technical document (CTD), which contains comprehensive information on the ADME properties of the molecule in the context of its efficacy, safety and risk for drug interactions. This presentation will focus on those aspects, including examples to illustrate how the ADME data package, integrated with other nonclinical and clinical data compiled in the IND or CTD, supports the stated risk/benefit profile of the new drug.
SC3.2 Pharmacology and Translational Aspects | Mirjam Trame
Open to view video.
Open to view video.
Abstract not available.
SC3.3 A Successful Preclinical Toxicology Package|Shaji Theodore
Open to view video.
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.
Certificate
No credits available | Certificate available
No credits available | Certificate available
Certificate of completion
