Best practice in the conduct of key nonclinical cardiovascular assessments in drug development: Current recommendations from the Safety Pharmacology Society

Abstract

A cardiovascular safety pharmacology assessment is routinely conducted prior to first administration of a new chemical entity or biopharmaceutical to man. These assessments are used to inform clinicians of potential effects in those initial clinical studies. They may also indicate more subtle effects having more relevance for longer term patient treatment studies such as a potential effect in a Thorough QT (TQT) study or a small persistent increase in blood pressure. Many pharmaceutical companies use the nonclinical studies for early decision making to avoid the clinical development of any compound likely to have a positive signal in a TQT study. These latter purposes generally require more sensitive assay systems and a confidence in their translation to man. At present it is often unclear whether any given study meets the standard required to convincingly detect these subtle effects. The Safety Pharmacology Society (SPS) brought together a group of over 50 experts to discuss best practices for dog and monkey cardiovascular assessments in safety pharmacology and toxicology studies in order to build overall confidence in the ability of a study to test a given hypothesis. It is clearly impossible to dictate a very specific standard practice for assays which are conducted globally in very different facilities using different equipment. However it was clear that a framework could be described to improve comparison and interpretation. Recommendations can be summarized on the basis of three key criteria: 1) know your study population quantitatively and qualitatively, 2) know how well your current study matches the historical data and 3) support your conclusions on the basis of the specific study's determined ability to detect change.