Regulatory Forum Opinion Piece*

Abstract

It is the author’s opinion that an experienced pathologist need not always be present at necropsy for safety studies to support development of large or small molecules. Reasons why an experienced pathologist need not be present in the room for every study as well as the value of necropsy attendance as a training opportunity for less experienced pathologists are presented. However, there are studies for which an experienced pathologist should be in attendance at necropsy and examples of these types of studies are listed.

Necropsies conducted to support development of small and large molecules are required by the U.S. Food and Drug Administration’s Good Laboratory Practice (GLP) regulations (21CFR58), addressed in International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines, and are typically conducted according to the GLP-required study protocol and standard operating procedures (SOPs) by technical staff accustomed to routinely differentiating normal from abnormal organ changes. In addition, these staffs are trained in GLP compliance, including documentation requirements. Typically, staff members have been trained by or have gained additional on-the-job training under the direction of, experienced pathologists. SOPs for the documentation of necropsy observations, including the format and lexicon to be used to describe observations, are usually written by or critically reviewed by pathologists. Lastly, facilities conducting these studies most often have experienced pathologists on-site, who can be called to attend the necropsy if unusual or unexpected observations are encountered. For these reasons, an experienced pathologist need not always be present in the necropsy room for safety studies to support development of large or small molecules.

Gosselin et al. (2011) opined that experienced or board-certified toxicologic pathologists should be readily available to the necropsy team but not necessarily in the same room. These authors felt that the role of necropsy pathologist could be fulfilled by veterinary pathologists who are studying for boards or by clinical veterinarians with industry experience and some pathology training. This recommendation seems appropriate for most standard safety studies. Additionally, fulfilling the role of necropsy pathologist in an industry setting is necessary for a new graduate from a residency program or a newly boarded pathologist to become an experienced pathologist. The ability to describe necropsy observations is learned during residency training. Consistent recording of observations and, equally important, not recording variations in normal appearance as findings, is often learned through on-the-job industry experience, including attending necropsies and having responsibility for correlating macroscopic observations to microscopic findings.

However, there are small- and large-molecule studies for which an experienced pathologist should be present at necropsy. Examples of situations in which the presence of an experienced pathologist in the necropsy room is recommended include:

Safety studies conducted in animal models of human disease. Frequently, the necropsy team for the safety study will not be familiar with the model and findings related to the induced disease. However, often there is a pathologist who has been working with the discovery and development teams who is familiar with background findings in the model. This pathologist is most apt to detect subtle test article–related effects against the disease background and should be present at necropsy to facilitate appropriate sampling and documentation of observations.

Safety studies conducted in animals that are treated so as to be immunocompromised. Similar to the situation for models of disease, findings related to immunocompromise or infections and not the test article are often present. Sometimes, these findings related to immunocompromise and infection may obscure subtle test article–related effects. If the necropsy team has not worked with similar immunocompromised animals, a pathologist experienced with immunocompromised animals should be present at necropsy.

Safety studies conducted in species or strains that are not routinely used and for which the necropsy team does not have recent experience. Studies may be conducted in species or strains with which the necropsy team has infrequent, limited, or no experience. In these situations, the presence of an experienced pathologist in the necropsy room can help assure that abnormal observations are recorded and that normal variations are not recorded as lesions.

Safety studies requiring sampling of tissues not usually sampled by the necropsy team or requiring nonstandard, specialized sampling. Although not common, there are situations where nonstandard sampling is planned and described in the protocol as for studies with a stereology end point. To meet the study objectives, it is often necessary for a pathologist trained in sampling for these studies to be present at necropsy.

There are nonregulated (exploratory) studies for which an experienced pathologist should be present at necropsy. Often, these studies are part of a new program for which there is no experience with the target. The study pathologist who may be part of the discovery team, or an experienced pathologist should be present at necropsy to capture early learnings. Later, it may be highly beneficial for a pathologist familiar with the target and program to be present at the necropsies for the initial regulated studies. This pathologist will assure consistency in recording observations and will be in the best position to recognize and communicate to the team target-related observations that have been seen previously versus new observations that appear in the toxicity study at hand.

In summary, an experienced pathologist does not always need to be present in the necropsy room for safety studies involving small and large molecules. However, there are situations where the study plan should include the presence of an experienced pathologist throughout necropsy.