Artificial intelligence and digital pathology: clinical promise and deployment considerations.

Artificial intelligence (AI) presents an opportunity in anatomic pathology to provide quantitative objective support to a traditionally subjective discipline, thereby enhancing clinical workflows and enriching diagnostic capabilities. AI requires access to digitized pathology materials, which, at present, are most commonly generated from the glass slide using whole-slide imaging. Models are developed collaboratively or sourced externally, and best practices suggest validation with internal datasets most closely resembling the data expected in practice. Although an array of AI models that provide operational support for pathology practices or improve diagnostic quality and capabilities has been described, most of them can be categorized into one or more discrete types. However, their function in the pathology workflow can vary, as a single algorithm may be appropriate for screening and triage, diagnostic assistance, virtual second opinion, or other uses depending on how it is implemented and validated. Despite the clinical promise of AI, the barriers to adoption have been numerous, to which inclusion of new stakeholders and expansion of reimbursement opportunities may be among the most impactful solutions.

Bridging the Gap: The Critical Role of Regulatory Affairs and Clinical Affairs in the Total Product Life Cycle of Pathology Imaging Devices and Software.

Manufacturers of pathology imaging devices and associated software engage regulatory affairs and clinical affairs (RACA) throughout the Total Product Life Cycle (TPLC) of regulated products. A number of manufacturers, pathologists, and end users are not familiar with how RACA involvement benefits each stage of the TPLC. RACA professionals are important contributors to product development and deployment strategies because these professionals maintain an understanding of the scientific, technical, and clinical aspects of biomedical product regulation, as well as the relevant knowledge of regulatory requirements, policies, and market trends for both local and global regulations and standards. Defining a regulatory and clinical strategy at the beginning of product design enables early evaluation of risks and provides assurance that the collected evidence supports the product's clinical claims (e.g., in a marketing application), its safe and effective use, and potential reimbursement strategies. It is recommended to involve RACA early and throughout the TPLC to assist with navigating changes in the regulatory environment and dynamic diagnostic market. Here we outline how various stakeholders can utilize RACA to navigate the nuanced landscape behind the development and use of clinical diagnostic products. Collectively, this work emphasizes the critical importance of RACA as an integral part of product development and, thereby, sustained innovation.

Quantitative Image Analysis for Tissue Biomarker Use: A White Paper From the Digital Pathology Association.

Tissue biomarkers have been of increasing utility for scientific research, diagnosing disease, and treatment response prediction. There has been a steady shift away from qualitative assessment toward providing more quantitative scores for these biomarkers. The application of quantitative image analysis has thus become an indispensable tool for in-depth tissue biomarker interrogation in these contexts. This white paper reviews current technologies being employed for quantitative image analysis, their application and pitfalls, regulatory framework demands, and guidelines established for promoting their safe adoption in clinical practice.

A Regulatory Science Initiative to Harmonize and Standardize Digital Pathology and Machine Learning Processes to Speed up Clinical Innovation to Patients.

Unlocking the full potential of pathology data by gaining computational access to histological pixel data and metadata (digital pathology) is one of the key promises of computational pathology. Despite scientific progress and several regulatory approvals for primary diagnosis using whole-slide imaging, true clinical adoption at scale is slower than anticipated. In the U.S., advances in digital pathology are often siloed pursuits by individual stakeholders, and to our knowledge, there has not been a systematic approach to advance the field through a regulatory science initiative. The Alliance for Digital Pathology (the Alliance) is a recently established, volunteer, collaborative, regulatory science initiative to standardize digital pathology processes to speed up innovation to patients. The purpose is: (1) to account for the patient perspective by including patient advocacy; (2) to investigate and develop methods and tools for the evaluation of effectiveness, safety, and quality to specify risks and benefits in the precompetitive phase; (3) to help strategize the sequence of clinically meaningful deliverables; (4) to encourage and streamline the development of ground-truth data sets for machine learning model development and validation; and (5) to clarify regulatory pathways by investigating relevant regulatory science questions. The Alliance accepts participation from all stakeholders, and we solicit clinically relevant proposals that will benefit the field at large. The initiative will dissolve once a clinical, interoperable, modularized, integrated solution (from tissue acquisition to diagnostic algorithm) has been implemented. In times of rapidly evolving discoveries, scientific input from subject-matter experts is one essential element to inform regulatory guidance and decision-making. The Alliance aims to establish and promote synergistic regulatory science efforts that will leverage diverse inputs to move digital pathology forward and ultimately improve patient care.

Computational pathology definitions, best practices, and recommendations for regulatory guidance: a white paper from the Digital Pathology Association.

In this white paper, experts from the Digital Pathology Association (DPA) define terminology and concepts in the emerging field of computational pathology, with a focus on its application to histology images analyzed together with their associated patient data to extract information. This review offers a historical perspective and describes the potential clinical benefits from research and applications in this field, as well as significant obstacles to adoption. Best practices for implementing computational pathology workflows are presented. These include infrastructure considerations, acquisition of training data, quality assessments, as well as regulatory, ethical, and cyber-security concerns. Recommendations are provided for regulators, vendors, and computational pathology practitioners in order to facilitate progress in the field. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Digital Imaging and Communications in Medicine Whole Slide Imaging Connectathon at Digital Pathology Association Pathology Visions 2017.

As digital pathology systems for clinical diagnostic work applications become mainstream, interoperability between these systems from different vendors becomes critical. For the first time, multiple digital pathology vendors have publicly revealed the use of the digital imaging and communications in medicine (DICOM) standard file format and network protocol to communicate between separate whole slide acquisition, storage, and viewing components. Note the use of DICOM for clinical diagnostic applications is still to be validated in the United States. The successful demonstration shows that the DICOM standard is fundamentally sound, though many lessons were learned. These lessons will be incorporated as incremental improvements in the standard, provide more detailed profiles to constrain variation for specific use cases, and offer educational material for implementers. Future Connectathon events will expand the scope to include more devices and vendors, as well as more ambitious use cases including laboratory information system integration and annotation for image analysis, as well as more geographic diversity. Users should request DICOM features in all purchases and contracts. It is anticipated that the growth of DICOM-compliant manufacturers will likely also ease DICOM for pathology becoming a recognized standard and as such the regulatory pathway for digital pathology products.

Whole Slide Imaging Versus Microscopy for Primary Diagnosis in Surgical Pathology: A Multicenter Blinded Randomized Noninferiority Study of 1992 Cases (Pivotal Study).

Most prior studies of primary diagnosis in surgical pathology using whole slide imaging (WSI) versus microscopy have focused on specific organ systems or included relatively few cases. The objective of this study was to demonstrate that WSI is noninferior to microscopy for primary diagnosis in surgical pathology. A blinded randomized noninferiority study was conducted across the entire range of surgical pathology cases (biopsies and resections, including hematoxylin and eosin, immunohistochemistry, and special stains) from 4 institutions using the original sign-out diagnosis (baseline diagnosis) as the reference standard. Cases were scanned, converted to WSI and randomized. Sixteen pathologists interpreted cases by microscopy or WSI, followed by a wash-out period of ≥4 weeks, after which cases were read by the same observers using the other modality. Major discordances were identified by an adjudication panel, and the differences between major discordance rates for both microscopy (against the reference standard) and WSI (against the reference standard) were calculated. A total of 1992 cases were included, resulting in 15,925 reads. The major discordance rate with the reference standard diagnosis was 4.9% for WSI and 4.6% for microscopy. The difference between major discordance rates for microscopy and WSI was 0.4% (95% confidence interval, -0.30% to 1.01%). The difference in major discordance rates for WSI and microscopy was highest in endocrine pathology (1.8%), neoplastic kidney pathology (1.5%), urinary bladder pathology (1.3%), and gynecologic pathology (1.2%). Detailed analysis of these cases revealed no instances where interpretation by WSI was consistently inaccurate compared with microscopy for multiple observers. We conclude that WSI is noninferior to microscopy for primary diagnosis in surgical pathology, including biopsies and resections stained with hematoxylin and eosin, immunohistochemistry and special stains. This conclusion is valid across a wide variety of organ systems and specimen types.

Current State of the Regulatory Trajectory for Whole Slide Imaging Devices in the USA.

The regulatory field for digital pathology (DP) has advanced significantly. A major milestone was accomplished when the FDA allowed the first vendor to market their device for primary diagnostic use in the USA and published in the classification order that this device, and substantially equivalent devices of this generic type, should be classified into class II instead of class III as previously proposed. The Digital Pathology Association (DPA) regulatory task force had a major role in the accomplishment of getting the application request for Whole Slide Imaging (WSI) Systems recommended for a de novo. This article reviews the past and emerging regulatory environment of WSI for clinical use in the USA. A WSI system with integrated subsystems is defined in the context of medical device regulations. The FDA technical performance assessment guideline is also discussed as well as parameters involved in analytical testing and clinical studies to demonstrate that WSI devices are safe and effective for clinical use.

Rocuronium blockade reversal with sugammadex vs. neostigmine: randomized study in Chinese and Caucasian subjects.

BACKGROUND: This study compared efficacy and safety of the selective relaxant binding agent sugammadex (2 mg/kg) with neostigmine (50 µg/kg) for neuromuscular blockade (NMB) reversal in Chinese and Caucasian subjects. METHODS: This was a randomized, active-controlled, multicenter, safety-assessor-blinded study (NCT00825812) in American Society of Anesthesiologists Class 1-3 subjects undergoing surgery with propofol anesthesia. Rocuronium 0.6 mg/kg was administered for endotracheal intubation, with 0.1-0.2 mg/kg maintenance doses given as required. NMB was monitored using TOF-Watch(®) SX. At second twitch reappearance, after last rocuronium dose, subjects received sugammadex 2 mg/kg or neostigmine 50 µg/kg plus atropine 10-20 µg/kg, according to randomization. Primary efficacy variable was time from sugammadex/neostigmine to recovery of the train-of-four (TOF) ratio to 0.9. RESULTS: Overall, 230 Chinese subjects (sugammadex, n = 119, neostigmine, n = 111); and 59 Caucasian subjects (sugammadex, n = 29, neostigmine, n = 30) had evaluable data. Geometric mean (95% CI) time to recovery to TOF ratio 0.9 was 1.6 (1.5-1.7) min with sugammadex vs 9.1 (8.0-10.3) min with neostigmine in Chinese subjects. Corresponding times for Caucasian subjects were 1.4 (1.3-1.5) min and 6.7 (5.5-8.0) min, respectively. Sugammadex 2 mg/kg was generally well tolerated, with no serious adverse events reported. There was no residual NMB or recurrence of NMB. CONCLUSION: Both Chinese and Caucasian subjects recovered from NMB significantly faster after sugammadex 2 mg/kg vs neostigmine 50 µg/kg, with a ~5.7 times (p < 0.0001) faster recovery with sugammadex vs neostigmine in Chinese subjects. Sugammadex was generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00825812.

Safety and efficacy of sugammadex for the reversal of rocuronium-induced neuromuscular blockade in cardiac patients undergoing noncardiac surgery.

BACKGROUND AND OBJECTIVE: The present randomized, safety-assessor blinded, placebo-controlled trial was designed to assess safety and efficacy of sugammadex, a novel selective relaxant-binding agent, in patients with underlying cardiovascular disease undergoing noncardiac surgery. METHODS: Overall, 116 patients (New York Heart Association class II-III) were randomized and received sugammadex 2.0 mg kg (n = 38), sugammadex 4.0 mg kg (n = 38) or placebo (n = 40) for reversal of rocuronium-induced neuromuscular blockade at reappearance of T2. Safety variables included heart rate, blood pressure and electrocardiogram characteristics, including rate-corrected QT (QTc Fridericia and QTc Bazett) interval. Efficacy was evaluated as time to recovery of the T4/T1 ratio to 0.9 after administration of sugammadex or placebo. RESULTS: There were no significant differences between groups in terms of QTc (Fridericia) interval. Three serious adverse events, one in each treatment group, considered to be possibly drug-related according to the investigator, were cases of mild QTc (Bazett) interval prolongation. Blood pressure and heart rate decreased after initiation of anaesthesia and remained stable in all groups up to 10 min after administration of study drug. Blood pressure was significantly higher (P < 0.05) in both sugammadex dose groups compared with placebo at 30 min. The decrease in heart rate from baseline (prestudy drug) was significantly greater in the 2.0 mg kg sugammadex group at 2 and 5 min, and, for both sugammadex groups, the increase at 30 min was greater compared with placebo. Both sugammadex doses resulted in considerably shorter time to recovery of the T4/T1 ratio to 0.9 compared with placebo. CONCLUSION: The findings indicate sugammadex 2.0 and 4.0 mg kg can be given safely and effectively for the reversal of rocuronium-induced neuromuscular blockade in patients with cardiovascular disease undergoing noncardiac surgery.