Theodore J Baird1, Michael J Caruso2, David V Gauvin2, Jill A Dalton2. 1. Safety Evaluation, Charles River Laboratories (CR/MWN), 54943 North Main St., Mattawan, MI 49071-9399, USA. Electronic address: theodore.baird@crl.com. 2. Safety Evaluation, Charles River Laboratories (CR/MWN), 54943 North Main St., Mattawan, MI 49071-9399, USA.
Abstract
INTRODUCTION: The concept of characterizing adversity in relation to administered test article dose and/or exposure within toxicology studies has long been considered a normal aspect of the drug safety evaluation enterprise. The typical way this is done in drug safety investigations is by examining study data, often with focus on clinical signs, clinical pathology and histopathology, to determine a No-Observable-Effect-Level (NOEL) and/or a No-Observable-Adverse-Effect-Level (NOAEL). Once established, these, with other information, may be used to identify a safe starting dose in human clinical trials. Although safety pharmacology (SP) is concerned to identify and characterize potentially "adverse" functional effects, NOEL, and particularly NOAEL, traditionally do not have application in SP study interpretation and reporting. METHODS: An anonymized survey of a contract research laboratory master schedule was undertaken to appreciate recent usage of these concepts in GLP (Good Laboratory Practice) cardiovascular, respiratory, and neurobehavioral safety studies. RESULTS: Results across the sample of studies (N = 635) generally confirmed application of appropriate dose selection strategies, as there was a very low proportion (<1%) of observed severe adverse events (antecedent observations ultimately associated with morbidity/mortality). Data further indicated either no mention of NOEL/NOAEL (50%), or alternately, explicit identification of NOEL (28%), or NOAEL (21%). The majority of times a NOAEL was identified, it was also the case that this coincided with the highest dose administered (e.g., there may have been drug-related findings, but these were considered non-adverse across the dose range). DISCUSSION: While the concept of adversity is certainly relevant to nonclinical SP studies, actual current practices appear to reflect a history which generally avoids toxicologically-oriented classifications such as NOAEL. Questions remain regarding the applicability of NOAELs to safety pharmacology studies, including, importantly, the specific circumstances under which such designations of adversity may be considered to add value to understandings of relative risk and risk mitigation in early human clinical trials.
INTRODUCTION: The concept of characterizing adversity in relation to administered test article dose and/or exposure within toxicology studies has long been considered a normal aspect of the drug safety evaluation enterprise. The typical way this is done in drug safety investigations is by examining study data, often with focus on clinical signs, clinical pathology and histopathology, to determine a No-Observable-Effect-Level (NOEL) and/or a No-Observable-Adverse-Effect-Level (NOAEL). Once established, these, with other information, may be used to identify a safe starting dose in human clinical trials. Although safety pharmacology (SP) is concerned to identify and characterize potentially "adverse" functional effects, NOEL, and particularly NOAEL, traditionally do not have application in SP study interpretation and reporting. METHODS: An anonymized survey of a contract research laboratory master schedule was undertaken to appreciate recent usage of these concepts in GLP (Good Laboratory Practice) cardiovascular, respiratory, and neurobehavioral safety studies. RESULTS: Results across the sample of studies (N = 635) generally confirmed application of appropriate dose selection strategies, as there was a very low proportion (<1%) of observed severe adverse events (antecedent observations ultimately associated with morbidity/mortality). Data further indicated either no mention of NOEL/NOAEL (50%), or alternately, explicit identification of NOEL (28%), or NOAEL (21%). The majority of times a NOAEL was identified, it was also the case that this coincided with the highest dose administered (e.g., there may have been drug-related findings, but these were considered non-adverse across the dose range). DISCUSSION: While the concept of adversity is certainly relevant to nonclinical SP studies, actual current practices appear to reflect a history which generally avoids toxicologically-oriented classifications such as NOAEL. Questions remain regarding the applicability of NOAELs to safety pharmacology studies, including, importantly, the specific circumstances under which such designations of adversity may be considered to add value to understandings of relative risk and risk mitigation in early human clinical trials.