Toxicologic Pathology Forum*: Opinion on Addressing Gaps in INHAND Terminology for Medical Devices—A Proposal to Add New Diagnostic Nomenclature

Abstract

Historically, safety and efficacy assessment of medical devices began and has continued as standards under the International Organization for Standardization (ISO) rather than under regulatory agency guidelines applied to developing other biomedical product classes. These parallel and unequal pathways have led to multiple and substantive differences in methods and endpoints to determine adverse biological responses among therapeutic classes. Toxicologic pathologists with medical device experience consider standardized nomenclature and diagnostic criteria for medical devices and device-containing combination products as a critical unmet need for nonclinical pathology evaluations. The International Harmonization of Nomenclature and Diagnostic Criteria for Lesions (INHAND) initiative has established globally accepted terminology for proliferative and nonproliferative lesions in various laboratory animal species. Experienced pathologists have identified that some existing INHAND terms for rodents and particularly nonrodents are already used or can be modified for use in medical device studies, but new terms for diagnostic features unique to medical device studies are needed to close gaps in existing INHAND nomenclature. The best approach to establishing appropriate INHAND terms for medical devices (and by extension, device-containing combination products) will be to develop and implement suitable terminology (modified and new, as warranted) to address unmet needs for this distinctive therapeutic class.

Keywords

implant INHAND medical device nomenclature safety assessment background findings

*This article is an opinion piece submitted to the Toxicologic Pathology Forum (TPF). This perspective is the particular view of the authors and does not represent an official position of the Society of Toxicologic Pathology (STP), British Society of Toxicological Pathology (BSTP), or European Society of Toxicologic Pathology (ESTP), nor should it be considered to reflect the opinions, policies, or positions of regulatory agencies or the authors’ employers/organizations. The Toxicologic Pathology Forum is designed to stimulate discussion of topics relevant to regulatory issues in toxicologic pathology. Readers of Toxicologic Pathology are encouraged to send their thoughts on TPF opinion articles or ideas for new discussion topics to toxicologicpathologyforum@toxpath.org

Introduction

As with all biomedical products, medical devices are subject to a battery of nonclinical efficacy and safety assessments prior to initial clinical testing. Historically, principles and practices for nonclinical assessment of medical devices have diverged substantially from nonclinical testing of other biomedical products. Among the most important differences are the accepted diagnostic nomenclature and lesion-grading criteria for medical devices compared to other therapeutic product classes. This opinion gives the historical background behind the separate but unequal safety assessment pathways and offers a proposal crafted by toxicologic pathologists experienced in the field of medical devices for improving the linguistic and scientific reproducibility and relevance of nonclinical safety assessments for medical devices.

Unique History of Medical Device Testing

The legal definition of a “medical device” incorporates a broad range of natural and synthetic materials that are intended to either diagnose or be used as temporary or life-long implants to diagnose, treat, support or replace organs or tissues damaged due to injury and disease, without using a chemical reaction or metabolism as a primary mechanism of action.²³ Regulatory oversight of medical devices did not begin in any country until the 20th century. In the United States, medical device regulations were first promulgated in the 1960s to 1970s, with the formation of the US Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH) in 1982 to oversee medical device registration.¹⁹ As early medical devices were often structurally simple natural and synthetic materials (e.g., metals and polymers), early device regulations focused on ensuring the physicochemical identity and consistency of the components. Early guidance documents were established through the International Organization for Standardization (ISO), a network of 172 national standards bodies based in Geneva, Switzerland. The ISO Technical Committee (TC) 194 (ISO/TC 194) was started in 1988 and is charged with “[s]tandardization of the approach to biological and clinical evaluation of medical and dental materials and devices together with standardization of biological test methods applicable to those materials and devices as well as good clinical practice principles to clinical investigations in humans of those devices.”¹¹ Membership in an ISO TC is generally limited to those who work for an entity that belongs to ISO or national standards bodies. Given this arrangement, membership in ISO/TC 194 is heavily weighted toward engineering and materials sciences experts (with some regulatory input) but typically includes little to no biological or any pathology expertise. As a result, pathology evaluation methods and nomenclature included in ISO standards are (1) typically rudimentary and/or inconsistent with currently accepted and expected nonclinical pathology protocols, and (2) do not represent the complex biological interactions between living tissues and implanted medical devices.

The currently accepted global standards in the ISO 10993 series and lateral standards are the focus of the biological evaluation of medical materials and devices.⁷ Pathologists who evaluate biological responses of tissues to medical devices most frequently use ISO 10993-1:2018⁹ for an overview of risk management; ISO 10993-6:2016¹⁰ for local, usually shorter-term implants; and ISO 10993-11:2017⁸ for evaluation of systemic effects of implants. Unfortunately, the semi-quantitative scoring rubrics and diagnostic nomenclature presented in the ISO 10993 series are not aligned with accepted nonclinical pathology norms.¹³

In the past few years, the FDA CDRH has begun issuing medical device-specific guidelines that reflect its scientific positions. For instance, a use guideline for ISO 10993-1²⁶ was initially released following the partial acceptance of ISO 10993-1:2018 guidance by the Agency. In 2023, the FDA also issued a guidance for considerations for animal studies evaluating medical devices (mostly those covered by ISO 10993-11:2017), which emphasized the need for use of good laboratory practices (GLP) principles.²¹ However, this guidance has content and implementation issues documented by the Society of Toxicologic Pathology (STP)¹⁵ and the Society of Quality Assurance.¹⁴ Currently, ISO 10993-6:2016 and 10993-11:2017 are used by the FDA as written.²⁰

In addition to inconsistencies in FDA guidance documents, currently CDRH has no plans to incorporate Standard for Exchange of Nonclinical Data (SEND)-formatted data sets into the requirements for medical device submissions. However, SEND-compliant data may be required for combination products, where “combination products” are medical devices incorporating one or more drugs (where “drug” means a biomolecule or small molecule component), the applications for which are primarily reviewed by the FDA Center for Biologics Evaluation and Research (CBER) or the FDA Center for Drug Evaluation and Research (CDER) when the drug component is the primary mechanism of action of the product.²⁴

Current Basis for Biological Evaluation Terminology Used for Medical Implant Studies

Except for the term “biocompatibility” (i.e., the ability of a material to perform with an “appropriate” host response in a specific situation), consensus definitions for medical device terms have not been comprehensively published, including nomenclature for the local and systemic biological responses of tissues to implanted devices. Currently, the medical device-related pathology diagnostic terms accepted by the FDA have been and continue to be set by the ISO 10993 series and lateral standards,^7,12 FDA documents (guidances^26,21 and webpages),²² country-specific legal definitions,^5,25 consensus terminology published following meetings sponsored by biomaterial societies,³¹ and biomaterial/bioengineering dictionaries,^18,30 none of which include meaningful representation from toxicologic pathologists involved in nonclinical medical device evaluation. Unsurprisingly, the available glossaries and definitions for biological-specific terms do not align with standard pathology nomenclature. Harmonizing nomenclature for medical devices has been recognized by toxicologic pathologists as a critical unmet need for research and development but more so for safety and risk assessment of medical device products.

Examples Demonstrating the Need for Consensus Terminology in Medical Device Pathology Reporting

Correctly identifying, diagnosing, and communicating adversity of lesions is a fundamental component of translatability of risk between animals and humans. The current ISO and related terms used to describe host responses to implanted medical devices rarely follow the preference for primarily descriptive (not interpretive) standard pathology nomenclature.⁴ For instance, medical device reports using ISO-based terminology often summarize implant findings as a (“typical”) foreign body response (FBR) without providing details of characteristic tissue changes within the report. An FBR does not have (and may never have) a consensus definition as a FBR is a top-level interpretation rather than a descriptive morphological diagnosis. Thus, pathology reports may fail to distinguish among the biologically discrete features of granulation tissue, granulomatous inflammation, and granulomas, or simply combine the entire response into the descriptor of FBR. In addition, the tissue response to implants typically changes over time, so the term FBR may include inflammation and tissue injury (e.g., edema, hemorrhage, necrosis, granulation tissue) observed at early time points as well as indolent chronic active inflammation and tissue reorganization (e.g., fibroplasia, fibrosis) at later time points. Furthermore, a common late-stage healing response is characterized by the presence of residual mononuclear cell aggregates, which are recorded according to current guidelines as “inflammation” (i.e., cells engaged in active tissue injury) rather than as “infiltrates” (i.e., cells engaged in immunosurveillance without inducing tissue damage). Thus, rather than accurately characterizing the chronic tissue response to the device, the current ISO standards emphasize maintenance of terminology continuity across time points, despite the important difference in the biological implications between “infiltration” and “inflammation.” Finally, clusters of lymphocytes organized into follicular patterns as “tertiary lymphoid structures” (TLS),²⁹ a chronic localized response reported for multiple implant materials,¹⁶ which may also be mistakenly reported as inflammation.

A diagnostic term of particular concern is “fatty infiltration,” which is used but not defined in ISO 10993-6:2016.¹⁰ In published literature, fatty infiltration (or fatty change) is now most often associated with nonalcoholic fatty liver disease and liver cirrhosis, and within the INHAND guides, “fatty change” is currently a morphological diagnosis for the liver. Importantly, adipocyte alterations in fatty tissues (e.g., bone marrow) are recorded using the descriptive morphological terms “cellularity, increased, adipocyte” or “cellularity, decreased, adipocyte,” as appropriate.⁶ In contrast, ISO uses “fatty infiltration” as a gradable parameter for subcutaneous, intramuscular, neural, and other tissue implants. However, “fatty infiltration” is irrelevant for subcutaneous implants due to the preexisting and abundant adipocytes in the subcutis. Moreover, the combined term “astrocytosis/fatty infiltration” as suggested for neural implants, improperly conflates two tissue responses that arise from different mechanisms. In our collective experience, adipocytes in skeletal muscle at sites of implantation are a relatively rare occurrence except for chronic timepoints, and likely represent a metaplastic change (i.e., conversion of one cell type to another type with different cytoarchitectural and functional attributes, similar to osseous or cartilaginous metaplasia). When it does occur, this apparent fatty influx likely reflects a reparative re-differentiation of mesenchymal cells pre-existing at the implantation site and not inward migration of adipocytes from contiguous tissue fields. Therefore, a more appropriate term than “fatty infiltration” should be identified, and use of that term should be restricted to intramuscular and possibly a few other soft-tissue-implantation sites. Moreover, the definition of the term should be accompanied by recommendations that dissuade its inappropriate usage, particularly for implants placed in fatty tissues such as the subcutis or the central or peripheral nervous systems.

As these examples show, numerous problems exist with the available ISO glossary of diagnostic terms and how they are applied to tissue responses. Poorly selected and applied nomenclature that lacks consensus definitions can cause errors and inconsistencies in generating, interpreting, and reporting microscopic data needed for hazard identification, and characterization as well as risk assessment.

Bridging the Gap Between Current INHAND Terms and Medical Device Evaluation Needs

In 2022, a Scientific and Regulatory Policy Committee (SRPC) working group of the STP concluded that “. . . the lack of a standardized nomenclature specific to biomaterials and variable application of the INHAND terminology fosters ambiguity in the microscopic criteria used in pathology evaluations for medical device and combination product nonclinical studies.”¹³ We concur that INHAND is the most appropriate pathway to develop a practical and cohesive glossary of terms to describe tissue changes associated with implantation of medical devices and device-containing combination products. Many toxicologic pathologists working with medical devices and combination products already apply existing INHAND terminology where feasible, most often in studies following the ISO 10993-11:2017 systemic toxicity standard and increasingly in studies following the ISO 10993-6:2016 standard for local tissue responses. However, existing INHAND guides do not describe the many unique biological responses associated with purposeful implantation of a foreign body (Table 1). The regulatory expectations for evaluating implanted medical devices warrant the generation of a new INHAND working group to devise diagnostic terms to properly describe these unique responses.

Table 1.

Additional considerations for an INHAND guide for medical devices and combination^a (device + “drug”^a) products.

• There is a very broad legal definition of what constitutes a “medical device” according to the FDA (Section 201(h)(1) of the Food, Drug and Cosmetic Act)

• Medical devices are tested in their “final finished form” (e.g. full size and function), which often requires use of large animals and life-sustaining activity usually precludes use of certain control groups

• Published spontaneous/background findings (historical control data) are lacking for some species or strains (e.g. chinchillas, hound dogs, sheep, etc.) commonly used for nonclinical testing of medical devices

• Procedure- and/or surgical-related findings frequently produce confounding tissue changes that must be differentiated from test article-related findings

• “Controls” are often approved devices or previously evaluated materials (positive or reference controls) that may have a different composition than the Test Article, and thus may induce a different tissue reaction

• Host responses to all biomaterials or for the same materials placed in different anatomic locations are not phenotypically identical and do not always represent a classic “foreign body response”

• The subcategory of “degradable” medical devices can be challenging due to the simultaneous occurrence of changing test article-related tissue reactions and the variable appearance and amount of the degrading implanted material over time

• For the subcategory of “degradable” devices, regulatory agencies often request a microscopic determination of the degree and/or completion of degradation, but this endpoint has multiple variables that need to be defined for each study

• For the subcategory of “nondegradable” devices, regulatory agencies often request a microscopic determination of the tissue integration status, but this assessment requires functional data

• The regulatory expectation for examination of regional draining lymphoid tissues (macroscopically and/or microscopically) has not been well defined

For combination products, “drug” represents the pharmacologically active (small molecule or biomolecule) component(s) associated with the medical device component.

We view INHAND nomenclature that addresses the nuances of unique findings associated with specific therapeutic categories as a natural extension of the completed special-purpose guides, similar to the upcoming nomenclature for fish and nonrodent ocular toxicity.³ A provisional group of medical device-focused pathologists from the STP, BSTP (British Society of Toxicological Pathology), ESTP (European Society of Toxicologic Pathology), JSTP (Japanese Society of Toxicologic Pathology), and STP–I (Society of Toxicologic Pathology—India) was formed in 2024 to discuss terminology gaps and develop a proposal for an INHAND special-purpose guide specific for medical devices and combination products. In February 2025, the global STPs approved establishment of an INHAND working group that will produce a publication of existing (with modifications, if warranted) and new terms for implant-related findings based on the format used in prior nonrodent INHAND guides. Rabbits rather than rodents are a commonly used species for many medical device studies, and the INHAND guide for rabbits² will be a valuable template, along with input from other nonrodent INHAND guides, for initially organizing terminology for medical devices. General pathology terminology (e.g., “inflammation” vs. “infiltrate,” “fibroplasias” vs. “fibrosis,” etc.) will be readily applied to medical devices, but we will likely require additional discussion for the evaluation of lymphoid tissue responses to implants.^13,16,27,28 Since many but not all medical devices are organ specific, we envision that implant and species variations organized by organ systems will be presented within a single guide, although multiple guides may ultimately be required. Therefore, diagnostic nomenclature for common implant sites such as bone, cardiovascular, cutaneous/subcutaneous tissues, eye, nervous systems (central and peripheral), and skeletal muscle will be incorporated with necessary adjustments from existing INHAND guides, and as required new terms will be defined in this new INHAND guide for medical devices.¹⁷

Other terminology modifications derived from existing INHAND guides will be driven by unique features of the tissue responses to medical devices (Table 1). Such distinctive responses, in many respects, are influenced by the unique attributes of medical devices and combination products, such as biomaterials with surface modifications to modulate inflammation, the use of less-common animal species/strains (e.g., hound dogs rather than inbred beagle dogs), and simultaneous evaluation of both safety and efficacy that often necessitates using an established animal model of a specific disease (e.g., induced bone defect in rabbits to test orthopedic devices). As with other INHAND guides, we anticipate that periodic revisions to the device terminology will be required as new materials and medical devices are introduced and our scientific understanding of tissues responses to implants improves. We also acknowledge that selected medical device studies may require some deviation from current INHAND nomenclature to accurately describe morphological features of unanticipated, atypical device-related biological responses, leaving the choice of the most appropriate diagnoses to the discretion of the study pathologist.² In such cases, it is incumbent on the study pathologist to explain the intended meaning of any diagnostic terms that deviate from the INHAND glossary.

Conclusions

To quote Mark Twain, “. . . the difference between the almost right word and the right word is really a large matter—‘tis the difference between the lightning-bug and the lightning.’”¹ Development of medical devices has long suffered from “not the right words” being used to describe and characterize local or systemic biological responses. The basic tools to rectify this deficiency already exist within the technical publications developed by the STP and the INHAND initiative, requiring modest modifications and additions to meet the unique needs of medical devices and device-containing combination products. The proposed medical device INHAND guide must be sufficiently flexible to address current biomaterials and tissue responses as well as accommodate any future device innovations. This new INHAND guide will also need to account for tissue changes in novel research animals with induced and/or spontaneously occurring diseases as well as a plethora of nonstandardized implant techniques causing variable and confounding surgical and/or procedure-related changes with or without tissue responses due to presence of secondary medical implants (e.g., sutures and staples within implant trauma).

Our proposed medical device INHAND guide should improve the accuracy, consistency, and reliability of diagnoses and hazard identification within and across studies as well as improve communication between pathologists, allied scientists, bioengineers, sponsors, regulatory agencies, and medical device innovation investors. Even though we are eager to address this significant deficiency in nonclinical diagnostic nomenclature, we recognize that adoption of such an INHAND guide will represent a fundamental change that is likely to clash with the long-standing twin beliefs deeply rooted in the historical ISO standards that (1) biological responses to all medical devices can be adequately captured using simple scoring rubrics with a few key terms, and that (2) comparing responses across devices (e.g., test article vs control) in a simple subtractive exercise comparing mean scores for the groups in question provides a number that accurately interprets the nature of any device-related biological responses. If nothing else, an INHAND guide for medical devices is needed to elevate the evaluation of biological responses to medical devices to the same level of scientific rigor and accuracy currently expected for nonclinical studies used in the safety evaluation of other biomedical products. A delay in establishing an INHAND guide for medical devices risks further divergence between the dueling systems (drugs vs. medical devices) for evaluating biological responses to test articles, with the two approaches increasingly colliding in the assessment of device-drug combination products.

Footnotes

Author Contributions

Prepared the initial draft (JCLS); with conceptual and early revision input from (LMW, BB, KAF). All authors contributed to final editing of the content. The analysis, conclusions, and opinions expressed in this article are solely those of the authors.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

JoAnn C. L. Schuh

Lyn M. Wancket

Brad Bolon

Kathleen A. Funk

Joanna M. Rybicka

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