Best practice considerations for nonclinical in vivo cardiovascular telemetry studies with alternative study designs in non-rodent species

Abstract

The recently published ICH E14/S7B Q&As incorporated an additional thorough QT (TQT) substitution path for compounds that are double negative in nonclinical studies (hERG and in vivo QT). To increase regulatory confidence in such an approach, general requirements for nonclinical telemetry studies were detailed in the Q&As that focus on model sensitivity, data analysis techniques, and clinical translation. Briefly, criteria for the integrated risk assessment include prescriptive in vitro hERG requirements, and an in vivo evaluation at sufficient multiples over the highest clinical exposure with demonstrated adequate sensitivity to detect an effect of a similar magnitude as a dedicated clinical QT study. Harmonization of best practices for a Latin square crossover study design were recently published by industry subject matter experts (SMEs) to ensure high quality QTc data to support an ICH E14/S7B Q&A 5.1 scenario that meets regulatory expectations. However, there is no industry consensus on best practices for alternate study designs (ascending dose, parallel groups, etc.) routinely utilized for oncology small molecule, large molecule, oligonucleotide, and peptide modalities. To increase industry consistency and ensure data quality, SMEs are collaborating to review current methodologies for alternative study designs where continuous data collection is required in implanted and jacketed telemetry studies. A survey was generated by members of the working group to gather information on alternative study designs employed, data analysis processes, QT interval correction and statistical methods, individual study and test facility sensitivity, and use of pharmacokinetic sampling. The most common current alternative designs included escalating dose (vehicle plus 3 doses levels, N = 4) and parallel (2–3 treatment groups plus concurrent vehicle, N = 4–8/group) which have been submitted to satisfy the ICH S7B, S6, S9, and to a limited extent, the S7B 5.1/6.1 Q&As. Escalating dose designs were typically applied to small molecules, whereas parallel designs were used to test oligonucleotides, large and small molecules. Data from this survey will be used as a starting point for the working group to recommend best practices for alternate study designs in the context of supporting the ICH E14/S7B Q&A 5.1 and 6.1 scenarios and build regulatory confidence in nonclinical QTc data.