The objective of the CIPA initiative is to facilitate the adoption of a new paradigm for assessment of clinical potential of TdP that is not measured exclusively by potency of hERG block and not at all by QT prolongation. The new CIPA paradigm will be driven by a suite of mechanistically based in vitro assays coupled to in silico reconstructions of cellular cardiac electrophysiologic activity, with verification of completeness through comparison of predicted and observed responses in human-derived cardiac myocytes. To the extent that the ongoing validation program is successful, we envision petitioning for corresponding changes to regulatory requirements for proarrhythmia assessment and these might include eliminating or waiving the need for the TQT.
What it is: Proposal to evaluate proarrhythmic risk based on mechanistic electrophysiologic understanding of proarrhythmia with two primary components:
What it is Not: CIPA will not replace need for careful clinical assessment of electrophysiologic effects in phase 1 ECG safety studies .
View more about CiPA here.
Develop voltage clamp protocols for core set of cardiac ion channel types.
Develop consensus in silico model to reconstruct electrophysiologic activity within a heart cell.
Investigate capabilities of human stem-cell derived cardiomyocyte assays to confirm findings of in vitro and in silico assays.
Plot course to revise ICH guidelines and provide input to the compounds selected to validate and test CIPA.