The ICH S7A Safety Pharmacology (Studies for Human Pharmaceuticals) guidance document states that the effects of the test substance on the respiratory system should be assessed appropriately. Respiratory rate and other measures of respiratory function (e.g., tidal volume or hemoglobin oxygen saturation) should be evaluated. Prior to the issuance of the guidelines, respiratory changes would have been assessed through clinical observation of the test system or during the conduct of an anesthetized cardiovascular model. These are generally not adequate to assess respiratory function as they do not quantify the required parameters in a suitable model, hence the need for an unanesthetized model.
Since the guidance was issued in 2001, a majority of the assessments have been made using plethysmography with test systems restrained in a head out chamber or a whole-body chamber. Developments over the years have also included the ability to combine measurements during the conduct of the cardiovascular study using telemetry.
However, twenty years on, questions remain about the utility and necessity of a standalone respiratory Safety Pharmacology study being a required core assessment. Non clinical safety data shows limited attrition related to the respiratory core battery assay. There have been a number of publications indicating that the translation of preclinical respiratory study findings to clinical adverse events is low. In addition, review publications have also found that few, if any at all, drugs have been terminated solely due to data from the core respiratory assessment. This certainly correlates with the experience that Attentive Scientists have found over the last 20 years of conducting many Safety Pharmacology studies at different laboratories. In fact, none of our team can recall unexpected findings occurring during a core battery respiratory study. Drug induced respiratory depression remains more difficult to detect under standard experimental conditions and in some cases other factors such as hypercapnia may be required. Overall, there is growing support to position the core respiratory study as a follow up/supplemental study where a more in-depth study could be designed based on findings from toxicology studies.
At Attentive Science, we critically assess what we do and how we do it on a daily basis. If the respiratory Safety Pharmacology study is moved from its current core battery position, there would be a significant reduction in test system usage and better align us all with the principles of the 3R’s. As we advance our scientific, knowledge we will always look for the alternatives and modifications to current trends. That is being Attentive.