Toxicologic Pathology, 42: 283-284, 2014 Copyright # 2013 by The Author(s) ISSN: 0192-6233 print / 1533-1601 online DOI: 10.1177/0192623313506880
Pathology Working Groups PETER C. MANN1
AND JERRY
H. HARDISTY2
1
2
Experimental Pathology Laboratories Northwest, Seattle, Washington, USA Experimental Pathology Laboratories, Research Triangle Park, North Carolina, USA ABSTRACT
Pathology Working Groups (PWG) are a specialized form of review consisting of a panel of expert pathologists who provide an independent, unbiased assessment of specific questions concerning study results. PWGs may concentrate on pivotal studies with controversial end points, address questions that are of concern to a regulatory agency, or compare the results of multiple studies that may have been conducted and evaluated by different laboratories and/or pathologists. The PWG does not review the entire study but always includes a preliminary review by a peer review pathologist. The PWG chairperson needs to thoroughly understand the issue in question, reviews all relevant data and study results, and is responsible for the organization and conduct of the PWG. The members of the PWG examine coded slides without knowledge of treatment group or previous diagnosis and arrive at a consensus diagnosis by majority vote. Once the results are decoded, the PWG evaluates the results and provides discussion and conclusions that are reflected in the final PWG report. Specific examples of PWG issues are provided. Keywords:
drug development; histopathology; preclinical safety assessment/risk management; regulatory affairs; risk assessment; risk identification; safety assessment.
PWGs are generally not required for data submitted to regulatory agencies but may be required on a study-by-study basis depending on the issues to be resolved by the agency. Environmental Protection Agency (EPA) Pesticide Regulation (PR) Notice 94-5 is the only regulatory requirement for a PWG review. In cases of reregistration of compounds, the EPA requires a peer review and PWG of all targets, a procedure they felt would improve the quality of decision making in classifying pesticide chemicals having carcinogenic potential. A PWG may be appropriate for studies with final reports, pivotal studies with controversial endpoints, to address questions that are of concern to a regulatory agency, or to compare the results of multiple studies that may have been conducted and evaluated by different laboratories and/or pathologists. Every PWG includes a preliminary review by a peer-review pathologist. This is generally a nonroutine retrospective review of all target organ tissues for the specific end points previously identified as the questions of interest for the PWG. The peer review evaluates the study pathologist’s findings for consistency and accuracy in the target tissue and identifies all the lesions that are relevant to the issue being addressed, including ‘‘borderline lesions’’ that might not otherwise be reviewed by the PWG. The PWG chairperson needs to thoroughly understand the issue in question. He or she reviews all the relevant data and study results and is responsible for the organization and conduct of the PWG. The PWG chairperson is generally not a voting participant of the PWG. The chairperson selects and prepares the material to be reviewed by the PWG, records the consensus findings of the panel, and serves as the author of a detailed pathology report which represents the PWG findings and conclusions. The PWG will need to review, as a minimum, all slides for which there were significantly different diagnoses by the study pathologist and the peer-review pathologist. The slides necessary for the PWG review are selected by the chairperson and
A Pathology Working Group (PWG) is a specialized form of review convened to answer a specific question or questions concerning study results. The PWG consists of a panel of expert pathologists selected from academia, private consultants, government, and industry. Members of the PWG may be veterinary, medical, or experimental pathologists selected for both their experience in toxicologic pathology and their expertise in the particular target organ (Boorman et al, 2002; Hardisty and Boorman, 1986; Mann et al, 2013). PWGs may be convened by study sponsors, consortiums, or at the request of government agencies. The PWG is generally conducted after the study has been finalized and thus requires full documentation. A PWG provides an independent, unbiased assessment of specific questions concerning study results. The PWG does not review the entire study: pathology peer review and data audits are utilized to provide these data. A PWG may be convened to address questions presented by regulatory authorities following Investigational New Drug (IND) or New Drug Application (NDA) submissions, to address issues that have resulted in a clinical hold on a candidate compound, or to establish appropriate nomenclature and diagnostic criteria for lesions of interest. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article. Address correspondence to: Peter C. Mann, Experimental Pathology Laboratories Northwest, 600 N 36th St., Suite 220, Seattle, WA 98103, USA; e-mail: [email protected]. Abbreviations: EPA, Environmental Protection agency; ESTP, European Society of Toxicologic Pathology; FDA, Food and Drug Administration; IND, Investigational New Drug; NDA, New Drug Application; MOA, mechanism of action; NOAEL, no observed adverse effect level; PCB, polychlorinated biphenyl; PPAR, peroxisome proliferator–activated receptor; PR, Pesticide Regulation; PWG, Pathology Working Groups; TCDD, tetrachlorodibenzodioxin. 283
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generally include all slides of the target for which a diagnosis was made by either the study pathologist or the reviewing pathologist (e.g., all liver tumors in all animals). In some cases, the PWG might review all slides of the selected target (e.g., all kidney sections from male rats). Many different issues may be addressed by a PWG. Some examples include the following:
Incidence of neoplasms occurring in a target tissue in oncogenicity studies (e.g., kidney or adrenal medulla); Comparison of proliferative liver lesions in multiple studies conducted with several polychlorinated biphenyl (PCB) compounds to understand relative toxicity; Comparison of heart lesions in rats given the same test article at 2 different laboratories and evaluated by 2 different pathologists who arrived at 2 different diagnoses (cardiomyopathy vs. degeneration/necrosis with fibrosis); No observed adverse effect level (NOAEL) for alveolar macrophages with metered-dose inhaler route of compound administration; Human relevance of rodent neoplasms (rat kidney, mouse lung, mouse liver) using a mechanism of action (MOA) framework approach; Relevance of low incidences of neoplasms occurring only in treated groups in 13-week toxicity studies (renal tubule tumors and malignant lymphoma); Misinterpretation of tissue artifacts as treatmentrelated effects (‘‘dark neurons’’ in the brain, formalin fixation artifacts in the testes); Comparison of open versus coded approaches to pathology evaluation.
The members of the PWG examine coded slides without knowledge of treatment group or previous diagnosis. Each member records his or her diagnosis on worksheets provided by the chairperson. At intervals during the PWG, each member is asked to voice his or her opinion (vote) concerning each diagnosis. The chairperson then records these consensus opinions— this record serves as the final PWG data. In instances where there is wide variance of opinion concerning a diagnosis, the panel will discuss the lesion, reexamine the slide, and vote again. There are usually 5 voting members on the PWG. The consensus diagnosis is determined for each slide examined by majority vote. After the chairperson records the final diagnoses, the results are decoded and tabulated for evaluation and discussion. No changes to the PWG diagnoses are permitted after the results have been decoded. The PWG then evaluates the results and provides discussion and conclusions that are reflected in the final PWG report. The PWG report should include the following:
Cover Page;
TOXICOLOGIC PATHOLOGY
Statement of Data Confidentiality Claims (if required by regulatory agency); Certification of Good Laboratory Practices; The PWG does not constitute a study; GLP Standards (40 CFR, Part 160) do not apply; EPA Flagging Criteria Statement (if required); PWG Participants’ Signature Page; Table of Contents; PWG Pathology Narrative; Introduction and Background; Materials and Methods; Results; Discussion; Conclusion; Appendices; Tabulation of original diagnoses in comparison to PWG diagnoses for each slide examined; Curriculum vitae of PWG members; References.
Over the past 20 years, PWGs have been utilized to successfully standardize criteria for upper respiratory tract lesions, to reassess the carcinogenicity of 2,3,7,8-tetrachlorodibenzodioxin (TCDD), to compare nasal olfactory mucosa in multiple studies, to provide guidance for risk assessment for ammonium perchlorate, to address concerns by the Food and Drug Administration (FDA) over renal findings with the antihypertensive Benicar, to establish consistent diagnostic criteria for tumors associated with peroxisome proliferator–activated receptor (PPAR) agonists, to review the mode of action and carcinogenicity of nitrapyrin, and to evaluate the proliferative lesions in the mammary glands of rats administered ammonium perfluorooctanoate. While the majority of PWGs are held in North America, the European Society of Toxicologic Pathology (ESTP) conducted a PWG on larynx squamous metaplasia in 2009. While PWGs are not a part of the routine review of the pathology portion of a study, they can be very helpful to retrospectively answer specific questions that arise during development of a new compound, and have been shown to be an effective and widely accepted component of the total development package. REFERENCES Boorman, G. A., Haseman, J. K., Waters, M. D., Hardisty, J. F., and Sills, R.C. (2002). Quality review procedures necessary for rodent pathology databases and toxicogenomic studies: The National Toxicology Program experience. Toxicol Pathol 30, 88–92. Hardisty, J. F., and Boorman, G. A. (1986). National toxicology program pathology quality assurance procedures. In Managing Conduct and Data Quality of Toxicology Studies (K. B. Hoover, J. K. Baldwin, A. F. Velner, C. E. Whitmire, C. L. Davies, and D. W. Bristol, eds.), pp. 263–69. Princeton Scientific Publishing, Princeton, NJ. Mann, P. C., and Hardisty, J. H. (2013). Peer review and pathology working groups. In Haschek and Rousseaux’s Handbook of Toxicologic Pathology (W. M. Haschek, C. G. Rousseaux, M. A. Wallig, B. Bolon, and R. Ochoa eds.), 3rd ed., pp. 551–64. Elsevier, Amsterdam, the Netherlands.
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Pathology Working Groups PETER C. MANN1
AND JERRY
H. HARDISTY2
1
2
Experimental Pathology Laboratories Northwest, Seattle, Washington, USA Experimental Pathology Laboratories, Research Triangle Park, North Carolina, USA ABSTRACT
Pathology Working Groups (PWG) are a specialized form of review consisting of a panel of expert pathologists who provide an independent, unbiased assessment of specific questions concerning study results. PWGs may concentrate on pivotal studies with controversial end points, address questions that are of concern to a regulatory agency, or compare the results of multiple studies that may have been conducted and evaluated by different laboratories and/or pathologists. The PWG does not review the entire study but always includes a preliminary review by a peer review pathologist. The PWG chairperson needs to thoroughly understand the issue in question, reviews all relevant data and study results, and is responsible for the organization and conduct of the PWG. The members of the PWG examine coded slides without knowledge of treatment group or previous diagnosis and arrive at a consensus diagnosis by majority vote. Once the results are decoded, the PWG evaluates the results and provides discussion and conclusions that are reflected in the final PWG report. Specific examples of PWG issues are provided. Keywords:
drug development; histopathology; preclinical safety assessment/risk management; regulatory affairs; risk assessment; risk identification; safety assessment.
PWGs are generally not required for data submitted to regulatory agencies but may be required on a study-by-study basis depending on the issues to be resolved by the agency. Environmental Protection Agency (EPA) Pesticide Regulation (PR) Notice 94-5 is the only regulatory requirement for a PWG review. In cases of reregistration of compounds, the EPA requires a peer review and PWG of all targets, a procedure they felt would improve the quality of decision making in classifying pesticide chemicals having carcinogenic potential. A PWG may be appropriate for studies with final reports, pivotal studies with controversial endpoints, to address questions that are of concern to a regulatory agency, or to compare the results of multiple studies that may have been conducted and evaluated by different laboratories and/or pathologists. Every PWG includes a preliminary review by a peer-review pathologist. This is generally a nonroutine retrospective review of all target organ tissues for the specific end points previously identified as the questions of interest for the PWG. The peer review evaluates the study pathologist’s findings for consistency and accuracy in the target tissue and identifies all the lesions that are relevant to the issue being addressed, including ‘‘borderline lesions’’ that might not otherwise be reviewed by the PWG. The PWG chairperson needs to thoroughly understand the issue in question. He or she reviews all the relevant data and study results and is responsible for the organization and conduct of the PWG. The PWG chairperson is generally not a voting participant of the PWG. The chairperson selects and prepares the material to be reviewed by the PWG, records the consensus findings of the panel, and serves as the author of a detailed pathology report which represents the PWG findings and conclusions. The PWG will need to review, as a minimum, all slides for which there were significantly different diagnoses by the study pathologist and the peer-review pathologist. The slides necessary for the PWG review are selected by the chairperson and
A Pathology Working Group (PWG) is a specialized form of review convened to answer a specific question or questions concerning study results. The PWG consists of a panel of expert pathologists selected from academia, private consultants, government, and industry. Members of the PWG may be veterinary, medical, or experimental pathologists selected for both their experience in toxicologic pathology and their expertise in the particular target organ (Boorman et al, 2002; Hardisty and Boorman, 1986; Mann et al, 2013). PWGs may be convened by study sponsors, consortiums, or at the request of government agencies. The PWG is generally conducted after the study has been finalized and thus requires full documentation. A PWG provides an independent, unbiased assessment of specific questions concerning study results. The PWG does not review the entire study: pathology peer review and data audits are utilized to provide these data. A PWG may be convened to address questions presented by regulatory authorities following Investigational New Drug (IND) or New Drug Application (NDA) submissions, to address issues that have resulted in a clinical hold on a candidate compound, or to establish appropriate nomenclature and diagnostic criteria for lesions of interest. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article. Address correspondence to: Peter C. Mann, Experimental Pathology Laboratories Northwest, 600 N 36th St., Suite 220, Seattle, WA 98103, USA; e-mail: [email protected]. Abbreviations: EPA, Environmental Protection agency; ESTP, European Society of Toxicologic Pathology; FDA, Food and Drug Administration; IND, Investigational New Drug; NDA, New Drug Application; MOA, mechanism of action; NOAEL, no observed adverse effect level; PCB, polychlorinated biphenyl; PPAR, peroxisome proliferator–activated receptor; PR, Pesticide Regulation; PWG, Pathology Working Groups; TCDD, tetrachlorodibenzodioxin. 283
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284
MANN AND HARDISTY
generally include all slides of the target for which a diagnosis was made by either the study pathologist or the reviewing pathologist (e.g., all liver tumors in all animals). In some cases, the PWG might review all slides of the selected target (e.g., all kidney sections from male rats). Many different issues may be addressed by a PWG. Some examples include the following:
Incidence of neoplasms occurring in a target tissue in oncogenicity studies (e.g., kidney or adrenal medulla); Comparison of proliferative liver lesions in multiple studies conducted with several polychlorinated biphenyl (PCB) compounds to understand relative toxicity; Comparison of heart lesions in rats given the same test article at 2 different laboratories and evaluated by 2 different pathologists who arrived at 2 different diagnoses (cardiomyopathy vs. degeneration/necrosis with fibrosis); No observed adverse effect level (NOAEL) for alveolar macrophages with metered-dose inhaler route of compound administration; Human relevance of rodent neoplasms (rat kidney, mouse lung, mouse liver) using a mechanism of action (MOA) framework approach; Relevance of low incidences of neoplasms occurring only in treated groups in 13-week toxicity studies (renal tubule tumors and malignant lymphoma); Misinterpretation of tissue artifacts as treatmentrelated effects (‘‘dark neurons’’ in the brain, formalin fixation artifacts in the testes); Comparison of open versus coded approaches to pathology evaluation.
The members of the PWG examine coded slides without knowledge of treatment group or previous diagnosis. Each member records his or her diagnosis on worksheets provided by the chairperson. At intervals during the PWG, each member is asked to voice his or her opinion (vote) concerning each diagnosis. The chairperson then records these consensus opinions— this record serves as the final PWG data. In instances where there is wide variance of opinion concerning a diagnosis, the panel will discuss the lesion, reexamine the slide, and vote again. There are usually 5 voting members on the PWG. The consensus diagnosis is determined for each slide examined by majority vote. After the chairperson records the final diagnoses, the results are decoded and tabulated for evaluation and discussion. No changes to the PWG diagnoses are permitted after the results have been decoded. The PWG then evaluates the results and provides discussion and conclusions that are reflected in the final PWG report. The PWG report should include the following:
Cover Page;
TOXICOLOGIC PATHOLOGY
Statement of Data Confidentiality Claims (if required by regulatory agency); Certification of Good Laboratory Practices; The PWG does not constitute a study; GLP Standards (40 CFR, Part 160) do not apply; EPA Flagging Criteria Statement (if required); PWG Participants’ Signature Page; Table of Contents; PWG Pathology Narrative; Introduction and Background; Materials and Methods; Results; Discussion; Conclusion; Appendices; Tabulation of original diagnoses in comparison to PWG diagnoses for each slide examined; Curriculum vitae of PWG members; References.
Over the past 20 years, PWGs have been utilized to successfully standardize criteria for upper respiratory tract lesions, to reassess the carcinogenicity of 2,3,7,8-tetrachlorodibenzodioxin (TCDD), to compare nasal olfactory mucosa in multiple studies, to provide guidance for risk assessment for ammonium perchlorate, to address concerns by the Food and Drug Administration (FDA) over renal findings with the antihypertensive Benicar, to establish consistent diagnostic criteria for tumors associated with peroxisome proliferator–activated receptor (PPAR) agonists, to review the mode of action and carcinogenicity of nitrapyrin, and to evaluate the proliferative lesions in the mammary glands of rats administered ammonium perfluorooctanoate. While the majority of PWGs are held in North America, the European Society of Toxicologic Pathology (ESTP) conducted a PWG on larynx squamous metaplasia in 2009. While PWGs are not a part of the routine review of the pathology portion of a study, they can be very helpful to retrospectively answer specific questions that arise during development of a new compound, and have been shown to be an effective and widely accepted component of the total development package. REFERENCES Boorman, G. A., Haseman, J. K., Waters, M. D., Hardisty, J. F., and Sills, R.C. (2002). Quality review procedures necessary for rodent pathology databases and toxicogenomic studies: The National Toxicology Program experience. Toxicol Pathol 30, 88–92. Hardisty, J. F., and Boorman, G. A. (1986). National toxicology program pathology quality assurance procedures. In Managing Conduct and Data Quality of Toxicology Studies (K. B. Hoover, J. K. Baldwin, A. F. Velner, C. E. Whitmire, C. L. Davies, and D. W. Bristol, eds.), pp. 263–69. Princeton Scientific Publishing, Princeton, NJ. Mann, P. C., and Hardisty, J. H. (2013). Peer review and pathology working groups. In Haschek and Rousseaux’s Handbook of Toxicologic Pathology (W. M. Haschek, C. G. Rousseaux, M. A. Wallig, B. Bolon, and R. Ochoa eds.), 3rd ed., pp. 551–64. Elsevier, Amsterdam, the Netherlands.
For reprints and permissions queries, please visit SAGE’s Web site at http://www.sagepub.com/journalsPermissions.nav.
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