The ICH-E14 guidance does indeed call for an “adequate representation” of female subjects in clinical trials, although not specifically for the Thorough QT (TQT) study. However, most TQT studies follow this recommendation and enroll sufficient numbers of female subjects. Interestingly, the issue of enrolling subjects with higher sensitivity to drug-induced QT prolongation and arrhythmia in TQT studies has been widely debated. Some also suggested that TQT studies with male-only subjects would reduce the well-known physiological variability in the QT interval and would therefore make these studies more efficient, requiring less subjects to meet the primary endpoint with sufficient statistical power. Nevertheless, the practice of “male-only” TQT studies has not been taken up and most TQT studies aim at enrolling equal proportion of male and female subjects.

Affirmative. There are several examples of drugs including antipsychotics and antiarrhythmic that had to be withdrawn from the market due to cardiotoxicity, in order to be reassessed and possibly redesigned. Some of these effects and adverse drug reactions (ADR), including unnecessary loss of lives, could have been prevented if dose-limiting toxicities had been appropriately assessed during development program. We have been party to a few drug-development programs where we were able to guide the development team on the DLT or the maximum tolerated doses based on serious cardiovascular ADRs, while maintaining a good balance between safety and efficacy.

The primary, regulatory mandated, cardiac risk biomarkers (BM) used in pharmaceutical drug development are the electrophysiology assays defined in the ICH-S7B (non-clinical) and ICH-E14 (clinical) guidance. The non-clinical biomarkers/assays include the in vitro ion channel (hERG, K+ current) electrophysiology tests, tissue repolarization assays (Action Potential Duration; APD) using cardiac Purkinje fibers, and in vivo animal QT and arrhythmia monitoring.

The E14 guidance is primarily focused on a single, well-designed, appropriately powered and conducted dedicated Phase I, called the Thorough QT (TQT) study. The primary endpoint and (surrogate) biomarker for arrhythmia risk required by E14 is the heart rate-corrected QT interval (QTc). Additional electrocardiographic parameters (Table 1) have been proposed by various industry and academic groups, however, none has yet gained a broad support from the clinical/scientific community or the relevant regulatory agencies.

The FDA, through its QT Interdisciplinary Review Ream (IRT) and Cardio-Renal Product Division is keeping an open mind (and eye) and has reiterated on multiple occasions that any new methodology that can detect the QT effect of moxifloxacin, the positive control commonly used in TQT studies, could be acceptable as a cardiac safety biomarker for drugs in development. Having said so, several new technologies (software and hardware, algorithms and devices) have been presented to the agency, however, as of today none has replaced or (exclusively) supported the QT endpoint in TQT studies.

A second category of cardiovascular safety biomarker in drug development include the serum biomarkers for myocardial ischemia and injury (e.g., cardiac troponins, CK-MB, BNP, etc), inflammation (hs-CPR, Ox-LDL, IL-18, etc), endothelial activation (sICAM, pSelectin), thrombosis (PAI-1, vWF, etc), pluck rupture (MMPs, PAPP), neurohormone activiation (BNP, NE), etc.

The third category is the cardiovascular imaging biomarkers, which include ECHO, MUGA, MRI, and other radionuclide scans.

For certain drug classes with known or suspected cardiotoxicity, such as the oncology and anti-inflammatory therapeutic areas, multiple-biomarker packages may be warranted. These BM packages, consisting of selected modalities from the above 3 categories of cardiovascular BM, are designed to improve overall sensitivity and specificity of signal detection, with the objective of supporting an early detection strategy of cardiovascular toxicity and liability of drugs under development.

Finally, we have recently seen the time-honored blood pressure monitoring emerging as a clinical safety biomarker for cardiovascular safety. Certain drugs and pharmacological classes have recently been associated with a BP effect, typically increase in either systolic, diastolic, or both BP elements. These BP effects translate, over a period of 5 to 10 years into a CV liability due to increased risk for atherosclerotic CV conditions, including coronary artery and cerebrovascular disease, resulting in debilitating, and possibly fatal, myocardial ischemia, myocardial infarction and strokes, to name only a few complications.

We are aware that the FDA has recently developed specific interest in BP monitoring and are currently developing some policies requiring systematic BP assessments in certain therapeutic area, including but not limited to oncology, diabetes, and cardiovascular. Newer technologies developed over the recent years allow an objective, centralized, and standardized assessment of ambulatory and office blood pressure and opened the possibility of monitoring patients from home using automated telemedicine solutions. Moreover, recently developed advanced and sophisticated technologies enable detecting early BP signals by monitoring central aortic pressure, arterial stiffness index, pulse wave velocity, etc., as biomarkers for drug-related vascular changes leading to atherosclerosis and increasing risk for, otherwise preventable, cardiovascular events.