Sponsor-CRO Practices That Facilitate the Creation of a High-Quality Pathology Report

Introduction

Contract research organizations (CROs) provide a multitude of valuable services and expertise to the pharmaceutical industry, government, and other organizations. One of those services is conducting nonclinical toxicology studies to assess the safety of chemical and biological entities intended as pharmaceuticals. An integral part of these studies is the generation and interpretation of pathology data. Both the CROs and the sponsors of these studies have a genuine interest in ensuring that the pathology data are accurate and that the reports are of high quality.

The goal of this article is to provide the sponsors’ perspectives on practices that affect the conduct of preclinical studies and that specifically facilitate sound technical and scientific execution for pathology components of those studies, leading to the creation of pathology reports of high quality. This perspective will be limited to topics that affect the pathology contributor report of toxicology studies covered by Good Laboratory Practices (GLP) and will not encompass every possible aspect of the sponsor-CRO relationship. The sponsor-CRO relationship must be a collaborative and nonadversarial relationship that balances the perspectives and needs of both CROs (Gosselin et al. 2011) and sponsors. The success of this relationship and the generation of a pathology report of high quality will greatly depend on thorough communication at all stages of a toxicology study. The peer review process provides the opportunity for a comprehensive review of pathology data by a second pathologist to ensure that all test article–related target organs and findings are accurately and consistently identified, diagnosed, interpreted, and scored. For the purposes of this article, the study pathologist and the peer review pathologist are generally assumed to be employees of the CRO and sponsor, respectively. However, situations in which the study pathologist and/or the peer review pathologist are not employees of the CRO or the sponsor will require even closer communication between the CRO and the sponsor.

Perspective

Prior to Placement and Initiation of Study at the CRO

To ensure the generation of pathology reports of high quality, sponsors should conduct a thorough evaluation of the CRO prior to placement of studies (Kopplin and Richter 2007). Sponsors and CROs should engage in communications of the procedures and processes that affect the generation of clinical and anatomic pathology data. Before placing studies, sponsors should fully communicate their expectations, visit the facilities, understand the training of personnel, and include as part of their evaluation the review of standard operating procedures (SOPs) governing animal euthanasia, blood collection, clinical pathology analyses, necropsy, histology, evaluation of pathology data, peer review, and creation of reports. Although there are many ways of performing a variety of these procedures and processes, the sponsor must be comfortable with the integrity of the processes that will be used to generate data. It is also useful to understand the capacity of the CRO to handle time-sensitive requests, such as histologic processing of target tissues from intermediate-dose groups. When feasible, this initial evaluation of CRO facilities and procedures affecting pathology data should include interaction with clinical and anatomic pathologists and be performed in conjunction with other personnel from the sponsor’s toxicology and quality assurance groups. This is of particular importance when placing studies covered by GLP regulations.

A critical part of all toxicology studies is the selection of the study pathologist(s) (clinical and/or anatomic) and necropsy pathologist(s). Although ensuring the competence of personnel is the responsibility of the CRO, the sponsor should fully understand the experience, training, and background of clinical and anatomic pathologists and necropsy personnel at each CRO. Because turnover of personnel is a normal occurrence in all organizations, sponsors should consider reviewing the training and qualifications of CRO personnel on a routine basis. The CRO should communicate to the sponsor when the study pathologist(s) is not an employee of the CRO as this may affect the location of the primary evaluation, the location of the peer review, and the communication between the study pathologist, CRO, and sponsor. The decision on how study pathologists will be selected for studies should be reached at the time that the sponsor and CRO first establish a relationship, should be reviewed on a periodic basis, and should be modified as needed. ACVP/ECVP certification is not a regulatory requirement as there are competent noncertified toxicologic pathologists. However, the sponsor must be knowledgeable about the training of the personnel evaluating toxicology studies and should be able to choose the minimal qualifications of the pathologists who will be interpreting the pathology data (anatomic and clinical pathology data). When necessary, the sponsor should be able to request specific pathologists with particular expertise, experience, and/or known performance attributes. In these circumstances, the sponsor should understand that requests for specific pathologists or for specific qualifications may result in delays, scheduling complications, or increased cost. A practical approach that balances the CRO’s need for flexibility and the sponsor’s study pathologist preference is to review on a periodic basis the available pathologists at the CRO and provide a list of the preferred pathologists to CRO management. Sponsors should also indicate to the CRO if their preference is to have a clinical pathologist interpret and report the clinical pathology data from toxicology studies.

Sponsors sometimes request that a pathologist supervise or be present during necropsies of animals from toxicology studies to guide or assist necropsy personnel during the necropsy procedures (Gosselin et al. 2011). Personnel who are not pathologists (i.e., veterinarians with necropsy experience) may also fill this role instead of pathologists. However, requesting the presence of a pathologist at necropsies of GLP studies should be at the discretion of the sponsor. Because necropsy findings do not undergo a peer review similar to that of microscopic pathology findings, it is of utmost importance that the sponsor is comfortable with the qualifications and experience of the necropsy personnel and with the necropsy procedures. Inaccurate or improperly recorded necropsy findings can have a negative impact on the quality of a toxicology study. Sponsors should also consider when it is appropriate to have a sponsor pathologist at necropsy.

It is our experience that providing information about the test article to the CRO, in particular the study pathologist(s), is clearly beneficial and facilitates the work of the study pathologist and the peer review pathologist. Despite the benefits, the amount and type of information provided should be at the discretion of the sponsor since the sponsor has a better grasp of the risks associated with unlimited sharing of information. Limiting the amount of shared information may result in an inadequate primary evaluation, a complicated pathology peer review, and costly delays in timelines. However, some sponsors limit the amount of information shared with the CRO because of concerns about unintended dissemination of intellectual property, to avoid discussions about the risk versus benefit of a compound within the report, and/or to avoid situations in which a study pathologist may feel inclined to replicate the results of previous studies with the same compound or from published or proprietary data on similar compounds. This latter situation is not unique to CROs as it may also be applicable to sponsor pathologists who perform primary evaluations. Information to consider providing to the CRO includes literature references, results or reports from previous toxicology or toxicokinetics (TK) studies with the same compound, and publicly available information on similar compounds and on-target genetically modified animals.

Sponsors should discuss with the CRO or study pathologist any preferred or requested lexicon in advance of the necropsy and microscopy evaluation. The use of consistent terminology across studies or standardized terminology facilitates the incorporation of pathology findings into regulatory documents and minimizes unnecessary questions from regulators that are specifically due to inconsistent terminology across studies of the same compound. This proactive communication of preferred lexicons will result in a more efficient pathology peer review and facilitate a report of high quality that fits the CRO’s and sponsor’s needs.

Numerical differences in spontaneous or background microscopic findings in data tables may be misinterpreted by others, particularly if the data tables are complicated. Therefore, sponsors should understand and discuss with the CRO how these spontaneous findings are recorded, the consistency of the recording practices, and how these findings are graded by pathologists at the CRO. This is of particular relevance when multiple studies supporting the same pharmaceutical program have been evaluated by different pathologists at the CRO or evaluated by pathologists at different organizations. Consistency in recording of spontaneous findings is important since historical data of control animal findings are frequently requested by regulatory reviewers or sponsors. It is of importance that spontaneous or test article–related microscopic findings are accurately and consistently recorded across studies to ensure pathology reports of high quality and avoid unnecessary delays of regulatory agency review due to inconsistencies between different studies. CROs should also consider establishing searchable databases of microscopic findings in control animals to assist in the interpretation and understanding of microscopic findings in toxicology studies.

Sponsors should notify the CRO in advance if a specific report format or style is necessary. This will facilitate writing the report and minimize unnecessary revisions. This proactive planning should include discussions on using interpretative versus descriptive language, use of in-text tables, presentation of unscheduled deaths, separating findings as primary versus secondary effects, the extent to which clinical and gross findings are to be correlated with microscopic findings, if there is a need for the pathology report to designate adverse effect levels, and the extent of study data integration (in-life, TK, etc.) with pathology data. How sponsors handle the characterization of pathology findings as adverse findings varies widely. This is due in part to the complex and subjective nature of the process (Lewis et al. 2002; Dorato and Englehardt 2005). Sponsors have different practices ranging from characterizing individual study findings as adverse (or nonadverse) to using a more integrated approach to determine the adverse level of the entire study data set (Dorato and Englehardt 2005). In our opinion, the NOAEL (no observed adverse effect level) should be determined in the context of the complete study data set and not within the pathology report.

The CRO and sponsor must agree before the start of the study on timely but realistic timelines for the primary evaluation and for the peer review so that there is adequate time assigned for these evaluations. CROs should communicate clearly to sponsors when proposed timelines are unreasonably short to avoid having a negative impact on the quality of the pathology evaluation. Furthermore, close communication between the sponsor and the CRO is needed to plan realistic timelines whenever there is a possibility of a large number of target tissues or when nonstandard evaluations are planned or possible, including cytologic evaluation of bone marrow, electron microscopy, immunohistochemistry, and other evaluations.

The decision to process all tissues from all animals to blocks and/or slides is driven by the study protocol, should be at the discretion of the sponsor, and can result in important benefits, particularly when timelines are important to the sponsor. The main benefit includes minimizing delays in scheduled timelines when intermediate-dose groups and/or recovery groups must be evaluated and additional test article–related lesions are identified by the peer review pathologist.

During Study Conduct and Evaluation of Data

It is essential that both the study pathologist and the sponsor’s pathologist participate and contribute to study design, to ensure that study objectives can be achieved. Intentional communication between the study pathologist and peer review pathologist should be established during study design and maintained during study execution and before the primary pathology evaluation begins at necropsy and prior to initiating microscopic evaluations. A plan of communication should include other individuals, such as clinical pathologists at the CRO and/or at the sponsor, who will also be involved in the primary evaluation or in the pathology peer review process (Morton et al. 2010). This plan should also take into consideration situations in which the peer review pathologist is not an employee of the sponsor. The study pathologist and the peer review pathologist should communicate freely and directly during the primary microscopic evaluation in a manner analogous to an ad hoc consult when a pathologist “walks down the hall” to talk with a colleague. This plan of communication should include how significant pathology findings, particularly unexpected adverse findings, will be communicated to the sponsor during the evaluation of data. We believe that direct communication of preliminary and significant pathology findings between the study pathologist and the peer review pathologist are essential and facilitate the exchange of scientific understanding in advance of the peer review, and it ultimately enhances the quality of the pathology report by assisting in the refinement of terminology, facilitating the exchange of ideas ahead of the peer review, and facilitating the understanding of these preliminary findings by the peer review pathologist ahead of the peer review. If significant findings are identified, there must be timely communication to the study director and sponsor’s study monitor. This aspect of the sponsor-CRO relationship is of critical importance since it may be necessary to report these findings promptly to regulatory agencies when the safety of patients is at risk.

The location of the pathology peer review should be determined in advance of the peer review. A peer review at the CRO facilitates better communication between study and peer review pathologists, avoids delays in time due to shipping of slides, and may avoid issues with transporting animal tissues across international borders. Sponsors should specify whether the sponsor or CRO peer review SOP will be followed. Alternately, the peer review process can be specified in the study protocol. Sponsors should notify the CRO in advance of what documents or data are needed during the pathology peer review to avoid delays in the peer review process.

There are other practices that CROs can implement during the conduct of the study and the evaluation of the data that would enhance the quality of the pathology report. For example, the quality of the pathology draft report would be enhanced by instituting some form of internal review by another CRO pathologist of data tables, reports, or even tissue sections prior to the sponsor’s peer review. Some CROs already have processes in place for such reviews, and we encourage this practice. CROs should also ensure that there is adequate cross-communication and sharing of study data between their scientists, for example, between the individuals tasked with interpreting the TK data, the clinical pathology data, and the anatomic pathology data. It is our experience that this cross-communication improves the quality of the pathology report but may not always occur in a timely or complete fashion.

During the Pathology Peer Review

The primary purpose of the peer review of the pathology data is to ensure that all test article–related target organs and findings are accurately and consistently identified, diagnosed, interpreted, and scored. The ultimate goal is to help the study pathologist generate a pathology report of high quality. To help achieve this goal, we provide recommendations below that in our experience facilitate the sponsor’s peer review of the pathology data. Independently of the location of the pathology peer review, the study pathologist and peer review pathologist should be readily available to each other for consultation or discussions. The study pathologist and peer review pathologist should prioritize the peer review process so they can perform their duties as efficiently as possible. The CRO should have available as early as feasible the agreed-upon documents prior to the pathology peer review. These documents include pathology data tables (organ weights, gross observations, and microscopic findings), draft anatomic pathology report, clinical pathology data tables, draft clinical pathology report, and in-life data such as clinical signs, body weights, and food consumption. Evaluation of data tables, including clinical pathology data and interpretation, can facilitate the pathology peer review and guide the peer review pathologist. Often, data tables are reviewed prior to the review of microscope slides and therefore allow a more efficient peer review. In some situations, peer review of the entire study, including treatment and recovery phases, is more efficient than peer reviewing in stages. This approach allows the peer review pathologist to better compare effects across treatment and recovery and minimizes the need to repeat the evaluation of tissues from the treatment phase of the study.

To facilitate communication during the pathology peer review, the peer review pathologist should clearly indicate to the study pathologist what comments or findings were substantive and which were nonsubstantive. Although it is ideal to focus on substantive comments that affect study outcome, both the study pathologist and the peer review pathologist should understand that the process of determining if findings affect the study outcome is subjective by nature. Therefore, both the study pathologist and the peer review pathologist must be willing to engage in collegial discussions to resolve differences of opinion as to the impact of a finding on the study outcome. It is not uncommon for the study pathologist and peer review pathologist to consult additional colleagues or the literature to understand study findings and help resolve differences. Through use of these additional tools and activities, the sponsor and CRO pathologists will more easily come to agreement of the impact of a pathology finding on the study and minimize the situations of undue sponsor influence. Feedback on the narrative of the pathology report should be focused on the appropriate description of the findings and the interpretation. However, feedback or corrections on writing style are appropriate if the writing style interferes with the clarity of the description and interpretation. Well-written reports will minimize requests for clarifications or explanations at the time of assembly of regulatory documents by the sponsor or review by the regulatory agencies. For a recent comprehensive review of the pathology peer review, see Morton et al. (2010).

In conclusion, effective interactions among the sponsor’s pathologists and CRO pathologists are critical for generating good-quality pathology reports. Two-way communication is a major factor in building a good relationship between the CRO and sponsor and should start before a study is placed at the CRO and continue seamlessly from the point of study design through study execution and through generation of a final pathology report of high quality. Other practices that will help in generation of a pathology report of high quality are the following: (1) sponsor understanding the pathology processes and training of personnel at the CRO; (2) establishing realistic timelines that can be adjusted whenever there are unexpected target tissues and nonstandard evaluations; (3) discussing and agreeing before the study starts how pathology (anatomic and clinical pathology) will be evaluated, peer reviewed, and reported; (4) sharing background test article information will aid the study pathologist’s interpretation of findings; (5) establishing internal quality reviews of the draft pathology data before the peer review starts; (6) ensuring that CRO personnel communicate well with each other during conduct of the study; and (7) facilitating direct collegial communication between the study and peer review pathologists. In the generation of a high-quality pathology report, the sponsor-CRO relationship must be a collaborative and nonadversarial relationship that balances the perspectives and needs of both parties.