The Study Pathologist’s Role in GLP Studies

Abstract

Results of early nonclinical “General Toxicology” studies are used to set a safe starting dose for first-in-human (FIH) clinical trials. In FIH trials, the research subjects are typically healthy volunteers who have little to gain but much to lose if a trial goes wrong. With that in mind, good laboratory practice regulations require that a standardized system be used for the conduct, documentation, and retention of study-related materials. The study pathologist, working within that system of standards, documentation, and oversight, is key to the identification of potential target organs of toxicity and other toxicologically significant findings.

From my perspective as a reviewer of nonclinical toxicology studies submitted to the U.S. Food and Drug Administration, the contribution of study pathologists is critical. That statement becomes obvious when one considers the role that nonclinical studies play in the drug development process. Early general toxicology studies are intended to identify organs that are targets for drug toxicity and determine the relationship between administered dose and/or systemic exposure and the incidence and severity of toxicological findings. Results of those studies are used to extrapolate to humans, in terms of setting a safe starting dose for first-in-human (FIH) clinical trials. Safety in clinical trials is always a major concern for the agency, but this is especially true in FIH trials, where the research subjects are typically healthy volunteers who have little to gain but much to lose if a trial goes wrong.

As I see it, the overarching purpose of good laboratory practice (GLP) regulations ¹ is to put in place, within laboratories that conduct nonclinical safety studies, a system of standard operating procedures (i.e., SOPs) and documentation that allows for the complete reconstruction of a study after the final report has been generated. Procedures to be standardized include, but are not limited to, required training of study personnel, study-related operations that are performed routinely by the laboratory, and peer review (if and when it occurs). Documentation of all study-related activities is critical. This includes not only documentation of SOP-related or protocol-driven activities but also documentation of deviations from expected practices as well as unanticipated events. Also to be documented is the follow-up of those deviations and the study director's conclusions as to the impact of the events.

Because the agency cannot provide direct oversight of every nonclinical safety study, the GLPs also include a requirement that each study be monitored by a quality assurance unit (QAU). For many scientists involved in nonclinical safety studies, having QAU looking over their shoulder is an aggravation. Even worse is being caught making a mistake by QAU. The point I try to make on this issue is that as a nonclinical reviewer, I do not expect that a study will be perfect. I understand that unexpected events will occur. So when QAU notices a deviation from an SOP or protocol, as hard as it may be, consider that they have actually improved the study by identifying an issue that may otherwise have gone unnoticed. As noted above, the important follow-up step is to document the event, any investigation, and the study director’s conclusion as to the effect of the deviation on the data validity.