Scientific and Regulatory Policy Committee Points to Consider: Review of the United States Food and Drug Administration (FDA) Guidance on Pathology Peer Review in Nonclinical Toxicology Studies.

In December 2021, the United States Food and Drug Administration (FDA) issued the final guidance for industry titled Pathology Peer Review in Nonclinical Toxicology Studies: Questions and Answers. The stated purpose of the FDA guidance is to provide information to sponsors, applicants, and nonclinical laboratory personnel regarding the management and conduct of histopathology peer review as part of nonclinical toxicology studies conducted in compliance with good laboratory practice (GLP) regulations. On behalf of and in collaboration with global societies of toxicologic pathology and the Society of Quality Assurance, the Scientific and Regulatory Policy Committee (SRPC) of the Society of Toxicologic Pathology (STP) initiated a review of this FDA guidance. The STP has previously published multiple papers related to the scientific conduct of a pathology peer review of nonclinical toxicology studies and appropriate documentation practices. The objectives of this review are to provide an in-depth analysis and summary interpretation of the FDA recommendations and share considerations for the conduct of pathology peer review in nonclinical toxicology studies that claim compliance to GLP regulations. In general, this working group is in agreement with the recommendations from the FDA guidance that has added clear expectations for pathology peer review preparation, conduct, and documentation.

Scientific and Regulatory Policy Committee Points to Consider: Fixation, Trimming, and Sectioning of Nonrodent Eyes and Ocular Tissues for Examination in Ocular and General Toxicity Studies.

A Working Group of the Society of Toxicologic Pathology's Scientific and Regulatory Policy Committee conducted a technical and scientific review of current practices relating to the fixation, trimming, and sectioning of the nonrodent eye to identify key points and species-specific anatomical landmarks to consider when preparing and evaluating eyes of rabbits, dogs, minipigs, and nonhuman primates from ocular and general toxicity studies. The topics addressed in this Points to Consider article include determination of situations when more comprehensive evaluation of the globe and/or associated extraocular tissues should be implemented (expanded ocular sampling), and what constitutes expanded ocular sampling. In addition, this manuscript highlights the practical aspects of fixing, trimming, and sectioning the eye to ensure adequate histopathological evaluation of all major ocular structures, including the cone-dense areas (visual streak/macula/fovea) of the retina for rabbits, dogs, minipigs, and nonhuman primates, which is a current regulatory expectation for ocular toxicity studies.[Box: see text].

Investigation of the use of microwave ablation with and without cooling urethral perfusion for thermal ablation of the prostate gland in canine cadavers.

OBJECTIVE: To investigate the use of microwave ablation (MWA) with cooling urethral perfusion and with no perfusion (MWA-UP and MWA-NP, respectively) for prostate gland ablation in canine cadavers. ANIMALS: Cadavers of 18 sexually intact male dogs. PROCEDURES: After technique refinement in 2 cadavers, laparotomy with ultrasound-guided MWA-UP (n = 8) or MWA-NP (8) of the prostate gland was performed in 16 cadavers. Normograde cystourethroscopy was performed before and after treatment; recorded images were reviewed in a blinded manner for scoring of urethral mucosal discoloration and loss of integrity. Difficulty with cystoscope insertion was recorded if present. Excised prostate glands were fixed for serial sectioning, gross measurements, and calculation of percentage ablation. Percentages of prostate tissue necrosis from MWA, denuded urethral mucosa, and depth of epithelial surface loss in an adjacent section of the colon were estimated histologically. Variables of interest were statistically analyzed. RESULTS: Difficulty with cystoscope insertion after treatment was significantly more common and scores for urethral mucosal discoloration and loss of integrity were significantly higher (indicating more severe lesions) for the MWA-NP group than for the MWA-UP group. The histologically assessed percentage of denuded urethral mucosa was also greater for the MWA-NP group. Overall median percentage prostate gland ablation was 73%; this result was not associated with prostate gland volume or chronological order of treatment. CONCLUSIONS AND CLINICAL RELEVANCE: MWA-UP induced subtotal thermal necrosis of prostate glands in canine cadavers while limiting urethral mucosal injury. Further study is required to optimize the technique and evaluate its safety and efficacy in vivo as a future curative-intent treatment for prostatic tumors in dogs.

Introduction to Special Issue on Ocular Pathology and Drug Development.

Dysfunction of the visual system remains a leading cause of human disability worldwide. Preclinical studies are a key component of efforts to develop drugs and devices to ameliorate visual impairment. Although new opportunities for the delivery of targeted ocular therapeutics have been created, clinical success has been confounded by unique challenges of drug development for the eye. This Special Issue brings together a broad range of articles that augment our current understanding of the visual system and highlight methods for assessing ocular toxicity and some of the current challenges in ocular drug development. Topics addressed include the anatomy, developmental anatomy, and/or immunobiology of the visual system and associated lymphoid tissues; animal models; methods for assessing ocular toxicity; spontaneous background and procedure-related microscopic findings and common artifacts in histologic sections of ocular tissues; and novel ocular drug delivery systems.

Opinion on Performing Pathology Peer-Review During the Global Pandemic: Challenges and Opportunities.

The coronavirus disease 2019 pandemic has affected business on numerous fronts in unprecedented and abrupt ways. From site closures and local "stay-at-home orders" to travel advisories and restrictions, the day-to-day practice of toxicologic pathology has been impacted dramatically and rapidly. A critical function of Toxicologic Pathologists is performing pathology peer review for nonclinical studies. Traditionally, corroborating the findings of histological assessment could be achieved through shipment of histopathological slides to the peer review pathologist, or by the peer review pathologist traveling to the location of the slides (eg, the test facility). Since early 2020, many pathologists have been unable to perform the latter due to local, regional, national, test facility, company, and/or personal restrictions. The disruption for some has been minimal, while others are working from home for the first time. We recommend that contingency plans for all peer review procedures and personnel should be in-place to accommodate sudden and unexpected workflow transitions. Now, more than ever, approaching peer reviews with enhanced adaptability will help ensure success.

Good Laboratory Practice in the Academic Setting: Fundamental Principles for Nonclinical Safety Assessment and GLP-Compliant Pathology Support When Developing Innovative Biomedical Products.

Development of new biomedical products necessitates nonclinical safety assessment in animals as a means of assessing potential risk to human patients. Pivotal nonclinical safety studies that support human clinical trials are performed according to Good Laboratory Practice (GLP) guidelines, which are designed to ensure that the study was conducted under carefully controlled conditions using standardized and validated procedures that will yield a reliable, reproducible, and traceable data set. The GLP guidelines established by different regulatory agencies address organizational structure, personnel responsibilities, personnel training practices, quality assurance (ensuring compliance), facilities, equipment, standard operating procedures, study documentation (record keeping), and record and sample retention. Academic institutions engaging in nonclinical safety assessment on-site have multiple options for implementing a GLP quality system. This article outlines the rationale supporting the use of a GLP-compliant or GLP-like quality system in academia and reviews key concepts needed to efficiently and effectively implement GLP in the academic setting. Emphasis is given to provision of GLP-compliant pathology support as (1) pathology data are an essential component of GLP nonclinical safety testing, (2) familiarity with pathology-related GLP procedures typically is gained first outside the academic setting, and (3) microscopic pathology diagnoses and interpretations require special accommodations to ensure that they are undertaken in a GLP-compliant fashion.

Practical Strategies for Navigating Toxicologic Pathology in One's Early Career and Beyond!

The toxicologic pathologist plays a vital role in the scientific community, using their unique blend of diagnostic and investigative skills to advance biomedical research, public health, drug discovery, or regulatory practices. But what exactly do toxicologic pathologists contribute? Where do these specialized professionals work? How can toxicologic pathologists maximize their efficiency and potential? To enlighten students and trainees, as well as early- or mid-career toxicologic pathologists, or even those approaching retirement, the Career Development and Outreach Committee of the Society of Toxicologic Pathology (STP) sponsored a career development workshop entitled "Practical Strategies for Navigating Toxicologic Pathology in One's Early Career…and Beyond!" in conjunction with the STP 37th annual symposium. The workshop featured toxicologic pathologists from contract research organizations and the pharmaceutical industry, who provided their perspectives on career preparation, evolving veterinary pathologist roles within various sectors of toxicologic pathology, the fundamentals of safety assessment, logistics of projects involving good laboratory practices, tools for effective interpretation and communication of anatomic and clinical pathology results, and a recap of scientific resources available to support the toxicologic pathologist in his or her journey. This article provides brief summaries of the talks presented during this career development workshop.

Historical Data: Histopathology Lesions Observed in the Eyes of Control Rabbits in Topical Ocular Administration and Contact Lens Studies.

Information on background changes in the ocular tissues of rabbits ( Oryctolagus cuniculus), a common species employed in ophthalmic toxicology studies, is sparse. This complicates interpretation of changes in light of small sample sizes on any single study. The purpose of this publication is to document the interstudy incidence of spontaneous or iatrogenic changes occurring in eyes of control rabbits. Photomicrographs of select lesions are provided. The data set was derived from a total of 54 studies conducted over an eleven-year period at Alcon Research Ltd., a Novartis Division, which featured topical ocular and contact lens routes of administration. It includes a total of 1,222 pigmented and albino New Zealand rabbits and a total of 2,084 eyes which were either untreated or treated with innocuous control articles. There were no noteworthy differences across routes of administration. Changes in anterior segment ocular and adnexal tissues were more common than in posterior segment ocular tissues. Overall, mononuclear cell infiltration was the most common finding. The retina was the posterior tissue most commonly observed with spontaneous changes, with folds and rosettes being the most common retinal finding. Retinal changes were more common in albino as compared to pigmented rabbits. Understanding the incidence and characteristics of spontaneous ocular lesions facilitates accurate and consistent diagnosis and data interpretation.

Use of Severity Grades to Characterize Histopathologic Changes.

The severity grade is an important component of a histopathologic diagnosis in a nonclinical toxicity study that helps distinguish treatment-related effects from background findings and aids in determining adverse dose levels during hazard characterization. Severity grades should be assigned based only on the extent (i.e., amount and complexity) of the morphologic change in the examined tissue section(s) and be clearly defined in the pathology report for critical lesions impacting study interpretation. However, the level of detail provided and criteria by which severity grades are assigned can vary, which can lead to inappropriate comparisons and confusion when evaluating pathology results. To help address this issue, a Working Group of the Society of Toxicologic Pathology's Scientific and Regulatory Policy Committee was formed to provide a "points to consider" article on the assignment and application of pathology severity grades. Overall, the Working Group supports greater transparency and consistency in the reporting of grading scales and provides recommendations to improve selection of diagnoses requiring more detailed severity criteria. This information should enhance the overall understanding by toxicologic pathologists, toxicologists, and regulatory reviewers of pathology findings and thereby improve effective communication in regulatory submissions.

A safety and immunogenicity study of immunization with hVEGF26-104/RFASE in cynomolgus monkeys.

INTRODUCTION: Vascular endothelial growth factor (VEGF) is pivotal in tumor angiogenesis and therapies targeting the VEGF axis are widely used in the clinic for the treatment of cancer. We have developed a therapeutic vaccine targeting human (h)VEGF165. hVEGF26-104/RFASE is based on the truncated protein hVEGF26-104 as antigen formulated in an oil-in-water emulsion containing the sulpholipopolysaccharide RFASE as adjuvant. Here we describe the toxicity and immunogenicity of this therapeutic vaccine in cynomolgus monkeys. METHODS: In total 54 cynomolgus monkeys were used and divided in 7 groups. Groups 1-3 were control groups, either receiving PBS alone (group 1), RFASE alone (group 2) or hVEGF26-104 alone (group 3). Animals allocated to groups 4-7 received hVEGF26-104 together with RFASE, but with varying doses of the antigen or the adjuvant. All animals were immunized four times with 2-week intervals and safety and immunogenicity were monitored until 3 days after the final immunization. RESULTS: Immunization induced an RFASE adjuvant dependent acute phase response. High titers of antibodies against hVEGF26-104 and cross-reactive with hVEGF165, were found in monkey sera, 28 days after primer immunization. These antibodies were able to inhibit the binding of the monoclonal antibody bevacizumab with hVEGF165 in a competition ELISA. Moreover, the biological activity of hVEGF165 could be inhibited by the addition of immunized monkey serum in a VEGF specific bioassay. Importantly, no adverse events commonly observed with VEGF neutralization were observed throughout the study. CONCLUSION: These data show that hVEGF26-104/RFASE can be safely administered in cynomolgus monkeys, induces the desired immune response and therefore support the clinical development of this vaccine.

Scientific and Regulatory Policy Committee Review: Review of the Organisation for Economic Co-operation and Development (OECD) Guidance on the GLP Requirements for Peer Review of Histopathology.

In 2014, the Organisation for Economic Co-operation and Development (OECD) issued guidance no. 16, Guidance on the GLP Requirements for Peer Review of Histopathology. The stated purpose of the guidance document is "to provide guidance to pathologists, test facility management, study directors and quality assurance personnel on how the peer review of histopathology should be planned, managed, documented, and reported in order to meet Good Laboratory Practice (GLP) expectations and requirements." On behalf of and in collaboration with the global societies of toxicologic pathology, the Society of Toxicologic Pathology initiated a review of OECD guidance no. 16. The objectives of this review are to provide a unified interpretation of the guidance, to recommend compliant processes for organizations to implement, and to avoid inconsistent process adaptations across the industry. This review of the guidance document is the product of a global collaboration with other societies of toxicologic pathology and provides a section-by-section international consensus view and interpretation of the OECD guidance on peer review.