International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) for Lesions in the Minipig

Abstract

The International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) is a global project establishing diagnostic criteria and nomenclature for both proliferative and nonproliferative changes in laboratory animals. Nonrodent working groups (NRWGs) have been established for the dog, nonhuman primate, minipig, and the rabbit. The Global Editorial and Steering Committee (GESC) oversees the activities of the INHAND projects and is composed of toxicologic pathologists from all of the participating societies. In 2012, INHAND GESC began a collaboration with the U.S. Food and Drug Administration (USFDA) in adapting INHAND terminology for standardized nonclinical data submission to the FDA. The Standard for Exchange of Nonclinical Data is an implementation of the Clinical Data Interchange Standards Consortium Study Data Tabulation Model for nonclinical studies. The NRWG for the minipig consists of toxicologic and diagnostic pathologists from Japan, North America, and Europe, and the group has 15 members including a GESC representative. The NRWGs are reviewing the applicability of the rodent nomenclature for the species and providing terminology unique for the species as well as determining rodent terminology not appropriate for the species. This information will be published with representative illustrations and references.

The International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) is a global project establishing diagnostic criteria and nomenclature for both proliferative and nonproliferative changes in laboratory animals. This initiative was started in 2005 by the Society of Toxicologic Pathology (STP) in collaboration with the European STP, which had worked with the Registry of Industrial Toxicology Animal-data (RITA) (Mann et al. 2012). In 2006, the BSTP (British Society of Toxicological Pahtology) and the JSTP (Janpanese Society of Toxicologic Pathology) joined the initiative, so that the project was truly global. The Global Editorial and Steering Committee (GESC) oversees the activities of the INHAND projects and is composed of toxicologic pathologists from all of the participating societies. In 2012, INHAND GESC began a collaboration with the U.S. Food and Drug Administration (USFDA) in adapting INHAND terminology for standardized nonclinical data submission to the FDA. The Standard for Exchange of Nonclinical Data (SEND) is an implementation of the Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model for nonclinical studies. This standard was developed by the CDISC SEND team for electronic submission of nonclinical data from animal toxicology studies. In 2013, the INHAND expanded the project, which initially focused on lesions in rats and mice, to include other commonly used nonrodent species, specifically minipig, monkey, dog, and rabbit.

For mice and rats, a group of experts was formed for each organ system, called an organ working group (OWG), with a published manuscript as an end product. A majority of the OWGs for mice and rats have completed their discussion and published manuscripts with terms for commonly observed background and compound-induced microscopic lesions observed in toxicity and carcinogenicity studies for each of the following organ systems:

hepatobiliary system

female genital system

male genital system

integumentary system

soft tissue system

nervous system

respiratory system

urinary system

mammary, Zymbal’s, preputial, and clitoral glands

Discussions are still in progress for rodent digestive, cardiovascular, endocrine, special senses, and lymphoid and hematopoietic systems (Keenan et al. 2015).

Nonrodent working groups (NRWGs) have been established for dog, nonhuman primate, minipig, and rabbit. The NRWG for the minipig consists of toxicologic pathologists from Japan, North America, and Europe. The group has 15 members including a GESC representative. The NRWGs are reviewing the applicability of the rodent nomenclature for the species and providing terminology unique for the species as well as determining rodent terminology not appropriate for the species. This information will be published with representative illustrations and references. Furthermore, major anatomical differences as compared to rodents and other species will be discussed. The strains of minipigs most used in toxicologic studies are the Göttingen and Yucatan, and therefore the group has focused on these strains.

The current use of terms in pathology reports in toxicologic studies using the minipig is partly taken from the terms established for rodents and also from the terms used in diagnostic pathology in pigs. Each company/university and country has developed their own preferred terms, which they have used for several decades. Initiatives to harmonize during the previous years have been established in several places and the internal/external peer review processes have also had the mission to align the terminology and grading of microscopic findings. The INHAND initiative is the first concerted effort toward a structured and robust process that has been successfully established, and harmonized nomenclature will be published for the nonrodent species in the near future.

The NRWG for the minipig is evaluating and considering the previously available nomenclature resources—appropriate literature as well as published INHAND rodent manuscripts, Global open Registry Nomenclature Information system, www.goReni.org) and Standardized System of Nomenclature and Diagnostic Criteria (SSNDC) Guides used by the STP and nomenclature available in databases with background data collected in the companies represented by members in the NRWG. The scope of work for the NRWG includes the nomenclature for:

nonproliferative lesions that are unique or have diagnostic criteria that differ from similar lesions in rodents,

spontaneous (background) and common induced lesions, and

proliferative and neoplastic lesions that may occur in chronic toxicity studies; proliferative lesions are very limited since minipigs are mostly used in studies from 1 week up to 1 year but should nevertheless be included in the work.

The members of the working group have had regular teleconferences starting in January 2014, where extensive discussions regarding terminology for all the organ systems have occurred. Members have discussed each individual rodent term and placed them into the following category with regard to minipig:

relevant—common,

relevant—uncommon,

relevant but not observed in the minipig,

not relevant for the minipig, and

relevant—induced.

In addition, the NRWG has added the terminology that is either specific to the minipig or not listed in the rodent terms but common in the minipig.

Alignment with the other NRWGs for monkey, dog, and rabbit is important and the goal is to have similar manuscripts. The NRWG for the minipig will begin the challenge of writing the manuscript soon and this should be published sometime after the OWGs have published all the organ systems for rodents.