Dr Boaz Mendzelevski, BioClinica
Proceedings from AHPPI’s conference on Risk Management in Early Phase Clinical Trials, 29 Oct 2015 (link).
This year marks the 10th anniversary of the introduction of the ICH E14 guideline which was introduced to provide a global standard in the clinical evaluation of QT/QTc interval prolongation and pro‑arrhythmic potential for non‑antiarrhythmic drugs. Following an initiative by the FDA discussions of the possibility of replacing the thorough QT (TQT) study with nonclinical proarrhythmia assays and QT assessment in early phase clinical studies are ongoing. The anticipation of revised ICH S7B and E14 guidelines created uncertainty amongst sponsors planning their exploratory medicine studies in man.
As the first speaker in this Cardiac Safety Session, Boaz briefly introduced the new cardiac safety paradigm including the proposed Comprehensive In vitro Proarrhythmia Assay (CIPA), multiple ion channel evaluation (MICE), in silico predictive modeling, cell-based assays and Phase 1 Intensive QT (IQT) studies.
The proposal is for IQT assessments to be added to routine Phase 1 SAD/MAD studies using exposure‑response modelling, i.e. the analysis of the relationship between drug plasma concentrations and QTc in place of the ICH‑E14 time-course analysis. The ER modelling has shown to be more effective and meet current statistical requirements with significantly fewer subjects.
Boaz reported on a recent IQ/CSRC Study and pointed out that this IQT validation study had several limitations – it investigated medicines with a marked effect on the QTc interval, but did not answer the question of how well the proposed model will perform in drugs with borderline QTc effects and drugs with known autonomic effects (QT:RR hysteresis). Moreover, drugs with long half‑life, delayed effects (PK:PD hysteresis), active metabolites, and drugs requiring up‑titration do not fit into this crossover study model, as they may require a parallel group design.
Amongst the issues to be resolved and/or agreed, he listed the confirmation of assay sensitivity without using a pharmacological positive control and how to otherwise exhibit sensitivity and specificity to identify both false positive and false negative effects. It is also not yet clear whether the E14 threshold of concern (upper 90% CI of 10 msec) will be retained in the new paradigm, and how will this affect the power required to clear the current or future regulatory end-point in IQT studies.
In concluding, Boaz reiterated that drug developers need to rule out QT prolongation or accept a QTc prolongation label, based on robust evidence. He advocated the conduct of intensive (SAD/MAD) IQT studies where appropriate and to consider a TQT study where an IQT design is not a good option.
Written by Dr Jörg Täubel, Richmond Pharmacology Limited. Jörg trained in clinical pharmacology and has been a principal investigator since 1995, conducting studies in patients and healthy volunteers ranging from first time in man (FTIM) to later phase studies particularly in cardiology, neurology, and gastroenterology. He provides expert advice in cardiac safety assessments and ethnic comparison studies. Jörg is an honorary fellow at St George’s University and his academic research is focussed on the role of hyperglycaemia in relation to sudden cardiac death in Type I diabetic patients. He is a member of AHPPI and AGAH and the EUFEMED scientific committee.