gms | German Medical Science

In different therapeutic areas the requirements for the assessment of the cardiovascular safety of medicinal products can differ considerably. The acceptability of a potential cardiovascular risk relates to the expected efficacy. Acceptance of a risk in a disease with a high mortality rate may not directly be transferable to other therapeutic fields.

The potential for life threatening ventricular arrhythmias should be characterised early in the clinical development of a medicinal product. It has to be reflected appropriately in the product information, avoiding both exaggeration and underestimation of the risk. According to the guidance documents ICH S7B and E14 preclinical investigations of the effect of drugs on QT are in many instances accompanied by clinical studies and analyses. These include Thorough QT/QTc studies and/or an expanded ECG safety evaluation in phase 3 studies including patients particularly at risk.

For medicinal products intended for the therapy or prevention of cardiovascular diseases, hard clinical endpoints are relevant for cardiovascular efficacy and safety. Cardiovascular safety and efficacy are assessed concomitantly. E.g. benefit risk assessment for an anticoagulant intended for the use in patients with atrial fibrillation depends on the close relation between cardiovascular efficacy and (vascular) bleeding risk.

Biomarkers and surrogate parameters can indicate specific safety concerns and identify patients at risk. They cannot prove cardiovascular safety of a medicinal product though. When the patient number becomes smaller and treatment duration shorter in a study that uses a biomarker or a surrogate as a primary endpoint, the safety database becomes less robust. This is particularly relevant for subgroups of special interest. Many of the antidiabetic drugs are approved based primarily on the effect on HbA1c. Efficacy and safety has not been directly demonstrated with respect to cardiovascular endpoints. Today, the requirements include in addition to preclinical testing a prospectively defined safety analysis. This can either by achieved by a metaanalytic approach or by a long term 18–24 months endpoint study. The latter approach is specifically required when there is suspicion of an adverse cardiovascular signal.

Taken together, the cardiovascular safety of a medicinal product is assesses based on the disease specific outcome and risk. It integrates the totality of preclinical and clinical information available for safety and efficacy.