Safety Pharmacology assessments have been a required component of the IND submission package since 2001 per ICH guidelines S7A/B. These studies are designed to tease out the potential for adverse events of clinically relevant doses on vital organ systems prior to commencing “first in human” clinical trials. The three vital organ systems in this scenario are the central nervous system (CNS), the cardiovascular system (CV) and the respiratory system. These studies usual commence once the subchronic toxicology investigations are underway using information from discovery and MTD/DRF studies to help select dose levels. The primary reason these studies are ideally conducted as standalone investigations, as opposed to regular inclusion in toxicology studies, is two-fold; dose selection and control of the experimental environment. Dose level selection for Safety Pharmacology studies is important as the range of doses should not exceed those producing mild to moderate toxicity following acute administration, ideally encompassing, and exceeding the primary pharmacodynamic/therapeutic range. Any overt toxic effects will most likely mask the subtle investigative nature of the Safety Pharmacology study endpoints which can confuse data interpretation. A controlled study environment includes limiting the number of test systems under investigation (compared to the numbers utilized in toxicology investigations), and laboratory activities (e.g., limiting extraneous noise, excessive entering and exiting the room, etc.).
The Attentive Science team have many years of experience in the field of Safety Pharmacology and many are recognized as experts. The core group’s experience was gained during their many years of tenure at European companies where they conducted GLP General Pharmacology studies (the forerunner to what we now know as Safety Pharmacology) for compounds entering the Japanese market from the mid-1980’s. This group were pioneers in offering GLP contract research services when the ICH S7 guidelines were introduced in 2001 and have been responsible for training many globally recognized Safety Pharmacology scientists.
The information collected from these studies are critical in the clinician’s goal of protecting their volunteers in Phase 1 trials. The results of Safety Pharmacology studies do not necessarily mean that development of a compound will cease. Knowledge of even mild side effects can help in ensuring the safety of the trial patients by allowing the clinical team to consider the potential for translation into humans when designing clinical studies. For example, our team conducted an in vivo cardiovascular safety pharmacology study that demonstrated a dose related “mild” hypotensive responses at clinically relevant doses. The clinical team were aware of this and were able to warn patients about possible hypostatic responses when getting out of bed. You do not want to see anyone pass out and injure themselves!
Our team have the experience and knowledge to enable you to make the best choices in Safety Pharmacology study design and help with the smooth progress of your compound through drug development and your IND submission.