Regulatory Perspective of Cardiovascular Risk Assessment
Safety Assessment
Henry Holzgrefe

Regulatory Perspective of Cardiovascular Risk Assessment

The harmonization of regulatory guidance for drug development traces its origins to the European Community (EC) in the mid 1980’s. The current governing body of record, known as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), was formed in 1990 at a joint meeting of regulatory agencies and industry associations from Europe, Japan and the US. The initial topics selected for harmonization were Safety, Quality and Efficacy and formed the basis for the approval of all new medicines.

The issue of cardiovascular safety, and in particular, the possible adverse effects of chemical entities that could affect cardiac repolarization, was highlighted by the antihistamine known as terfenadine. Terfenadine (Seldane™) was introduced to the market as the first nonsedating antihistamine in 1985 and had been used by over 100 million patients worldwide by 1990. Escalating regulatory scrutiny between 1990 and 1997 ultimately resulted in the withdrawal of this compound from the US market in February, 1998 due to its association with a rare and occasionally fatal cardiac arrhythmia called torsades de pointes (TDP). Indeed, it was the very broad consumer acceptance and demand for terfenadine that enabled investigators to identify the link between an apparently ‘safe’ drug and an occasionally lethal outcome. TDP is a polymorphic ventricular arrhythmia that, literally translated, means twisting of the points, where the QRS complex of the electrocardiogram (ECG) appears to rotate around the isoelectric baseline. During an episode of TDP the left ventricle of the heart does not contract properly, leading to a loss of blood pressure, oxygen delivery and if sustained for more than a few minutes, death.

As TDP is exceedingly rare, it was only because of experience with millions of patient prescriptions that the underlying cause (an interaction between terfenadine and erythromycin and ketoconazole) was identified. In the presence of the aforementioned compounds, terfenadine could occasionally be incompletely metabolized and the free terfenadine molecule could then interact with a particular cardiac ion channel (hERG) which governs potassium transport, resulting in delayed ventricular repolarization. Importantly, changes in cardiac repolarization can be detected by changes in the QT interval of the ECG, providing a readily accessible tool to screen for possible adverse drug effects. The clinical definition of TDP includes the requirement that a polymorphic arrhythmia be preceded by QT interval prolongation. So, QT interval prolongation is necessary, but not necessarily sufficient, to induce TDP. Confused? So was the drug development community.

In 2005, the pharmaceutical industry and the ICH incorporated these and other related findings into their drug development strategies, ultimately resulting in the adoption of the ICH S7B guideline: The non-clinical evaluation of the potential for delayed ventricular repolarization (QT-interval prolongation) by human pharmaceuticals and the human counterpart ICH E14: The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. These landmark documents ushered in a new period in drug development where new chemical entities were characterized by a uniform set of preclinical and clinical assays. Since the adoption of the S7B guidance, the incidence of unexpected QT prolongation in the clinic has steadily declined. This is noteworthy as clinical development ultimately entails many thousands of patient exposures, in stark contrast to the very limited number of preclinical observations which are possible during the early development period.

Even though the S7B guidance has been very effective at improving drug safety, it was primarily framed to address the effects of single acute administrations of small molecular entities and does not address the detection of possible QT prolonging effects which may only become apparent after persistent exposure and/or metabolic transformation. As drug developers continue to synthesize new entities and explore new classes of molecules, such as the so-called biologics (which includes the highly specific monoclonal antibodies), and pursue diseases which may persist over a lifetime and thus may require continuous treatment, like the metabolic disorders (diabetes, etc.), additional guidance has been provided which has both broadened and refined the initial scope of repolarization safety assessment.

Chief among these are the ICH M3 (Revision 2) Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals (June 2009), ICH S9 Nonclinical evaluation for anticancer pharmaceuticals (October 2009), and ICH S6 (Revision 1) Preclinical safety evaluation of biotechnology-derived pharmaceuticals (June 2011). The recent safety guidelines (S6 and S9) address specific indications and molecular structures and M3, a multi-disciplinary guideline, all broaden the potential scope of preclinical safety assessments, and in particular, acknowledge that such assessments may be integrated and performed as an integrated part of a toxicology study. This possibility at once embraces the animal welfare philosophy embodied in the 3Rs (Replacement, Refinement, and Reduction) of animal use and acknowledges the unique situation of safety assessment in a repeat-dose setting.

Repeat-dose safety assessment has emerged as a primary concern for both the drug-development community and regulatory bodies such as the FDA. At Charles River, these developments have fostered the development of new technologies, including Jacketed External Telemetry (JET) which allows classic repolarization safety parameters (such as the QT interval) to be seamlessly integrated into many classic toxicology study designs. A future article in this series will address the specifics of the QT interval, such as why it’s important, how it’s measured and how these measurements may be used to assess the cardiac safety of a new drug.