When you think of a pathologist, you may picture a scientist peering through a microscope, viewing slides and making notes about a disease state, then moving on to the next sample. Indeed, the classic role of many contract pathologists is to evaluate large numbers of tissue slides and author pathology reports. However at Covance, the Lead Optimization Pathology group plays a much greater role in drug development.
The Lead Optimization Pathology group offers Project Pathologists—a staff pathologist with therapeutic area expertise who is assigned to a project and intimately involved in supporting the early drug development in both efficacy and non-GLP toxicity studies. As ACVP board certified veterinary pathologists with Ph.D. degrees and past experience working in large pharmaceutical companies, the staff can offer in-depth pathology support for both small and big clients.
Creating efficiencies in study design
In the study design phase, project pathologists can help refine the animal model, recommend nonstandard pathology parameters to answer specific questions, or modify sampling methods to increase sensitivity. Screening paradigms also may be employed to help a client move through lead optimization in a timely and resource efficient manner.
For instance, take a case where consistent dose limiting toxicity is identified across multiple studies with different related test articles. Here, screening studies of shorter duration and examination of fewer tissues may allow for rapid screening of a large number of test articles. Or a study could include more optimal timing of clinical pathology and/or biomarker sampling to detect early changes. These techniques help identify the most promising lead candidate or confirm that the toxicity is likely on target.
A pathologist might suggest, for example, replacing a tedious and expensive quantitative morphometric digital slide evaluation of a renal disease model with a microscopic assessment, which may be a faster and less costly way to identify a subset of test articles that have the most promising pharmacology.
Integrating Pathology into multiple study points
Better project integration is also achieved by adding select pathology endpoints to in vivo pharmacology and other non-toxicology studies. For example, if specific toxicology liabilities are already known based on past studies, competitive intelligence or literature review, the client may be interested in evaluating a limited tissue set or some clinical pathology samples from the efficacy studies to move that risk assessment forward.
If unexpected toxicity is noted in an in vivo pharmacology study, the client can receive recommendations for pathology endpoints that can be added to the current study, or to future studies, to better understand the cause.
Clients can also benefit by better understanding of the mechanism of action of a toxicity, progression, reversibility, or whether a premonitory biomarker can be identified to help mitigate the risk. Especially in oncology, both the efficacy and toxicity of different dosing schedules can be explored by adding pathology endpoints to efficacy studies in tumor bearing animals. Or non-GLP toxicology studies can be conducted to compare the toxicity of a client’s test article to that of a competitor.
Customized partnerships to optimize cycle time
By assuming responsibility for the project, not just the study, a project pathologist becomes familiar with the toxicity profile for that test article or series of test articles which allows for more efficient evaluation of future studies by using the same terminology and grading schemes. One recent relationship lasted for over 2 ½ years and involved the evaluation of approximately two dozen test articles in a series of non-GLP toxicology studies with the goal of identifying a lead candidate.
The Covance Project Pathologist can become a valuable member of the client’s drug development team, assisting the client in comparing findings across studies and even participating in team meetings or co-authoring publications. Rapid decision making is a benefit for any study, so the project pathologist can be in frequent communication and provide preliminary data.
The relationship can even extend beyond traditional lead optimization toxicology work with the pathologist becoming the peer review pathologist for the First Human Dose-enabling GLP toxicology studies, especially for a smaller company that lacks its own staff pathologist.
The lead optimization process also can be customized to best serve the client needs. Being a dedicated, non-GLP laboratory allows for reduced costs, shorter time lines, and more flexible study designs. For some clients, moving through the lead optimization phase in shortest time possible is important. Based on the data, they can start designing the next study, propose smaller screening studies that can be conducted quickly, or oversee the evaluation of multiple simultaneous studies by other pathologists while still maintaining consistency.
For clients with a more limited budget, studies can be conducted in a step-wise manner, with a limited tissue list being selected only after evaluation of the live phase, clinical pathology, necropsy, and/or organ weight data. Alternatively tissue slides may be initially evaluated from just a subset of the animals. In projects that move on to GLP studies, the lead optimization project pathologist can share key findings with the Covance Early Development study directors and pathologists for a seamless transition.
The lead optimization team is accustomed working with other Covance departments and outsourcing partners, and consulting with scientists both in and outside of Covance, to provide seamless continuity. Even if the animal phase of the study was not conducted at Covance, tissues can be sent to the Covance for processing and evaluation, and a contributor report would be written for inclusion in the main study report.
From study design and planning to model expertise and consulting, Covance Project Pathologists love putting together the “pieces of the puzzle,” to answer drug development questions and ultimately help clients reach important development milestones.
For more information about how Covance can help you develop successful lead optimization pharmacology and toxicology strategies please contact us or visit our website for more information: www.covance.com/discovery.