Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science

Siddiqui, Mohammad Shadab; Harrison, Stephen A.; Abdelmalek, Manal F.; Anstee, Quentin M.; Bédossa, Pierre; Castéra, Laurent; Dimick‐Santos, Lara; Friedman, Scott L.; Greene, Katherine; Kleiner, David E.; Megnien, Sophie Jeannin; Neuschwander‐Tetri, Brent A.; Ratziu, Vlad; Schabel, Elmer; Miller, Veronica; Sanyal, Arun J.

doi:10.1002/hep.29607

Cited by 153 publications

(124 citation statements)

References 56 publications

(182 reference statements)

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“…Histologic evaluation of liver biopsies from patients with NAFLD has two essential roles in the setting of a clinical trial: to ensure that patients meet the eligibility criteria and to evaluate response to therapy . Steatosis, lobular inflammation and ballooning degeneration are the three main features that pathologists have used to measure disease activity and categorise NAFLD.…”

Section: Discussionmentioning

confidence: 99%

“…Defined as evidence of hepatic steatosis in the absence of secondary causes of fat accumulation in the liver, non‐alcoholic fatty liver disease (NAFLD) affects approximately one‐quarter of adults worldwide and it is estimated that disease‐related complications are increasing . NAFLD describes a spectrum of liver disease ranging from steatosis without hepatocyte injury (non‐alcoholic fatty liver) to non‐alcoholic steatohepatitis (NASH), which is characterised by steatosis coupled with inflammation and hepatocellular ballooning . Patients with NASH have an increased risk of liver‐related mortality and developing cirrhosis compared to those with non‐alcoholic fatty liver .…”

Section: Introductionmentioning

confidence: 99%

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Standardising the interpretation of liver biopsies in non‐alcoholic fatty liver disease clinical trials

Pai¹,

Kleiner²,

Hart³

et al. 2019

Aliment Pharmacol Ther

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Summary Background There is substantial variation in how histologic definitions and scoring systems of non‐alcoholic fatty liver disease (NAFLD) are operationalised. Aim To develop a consensus‐based framework for standardising histologic assessment of liver biopsies in clinical trials of NAFLD. Methods An expert panel of 14 liver pathologists and three hepatologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 130 items derived from literature review and expert opinion were rated by each panel member on a 1‐9 scale. Disagreement was defined as ≥5 ratings in the lowest (1‐3) and highest (7‐9) categories. Items were classified as inappropriate (median 1‐3.5 without disagreement), uncertain (median 3.5‐6.5 or any median with disagreement) or appropriate (median 6.5‐9 without disagreement). Survey results were discussed as a group before voting. Results Current measures of disease activity and fibrosis may not fully capture important features of non‐alcoholic steatohepatitis (NASH). Alternative methods to evaluate ballooning degeneration are needed. Panellists were uncertain whether portal inflammation, degree of steatosis and Mallory‐Denk bodies are important measures of disease activity. Furthermore, it was felt that current staging systems do not capture the full spectrum of fibrosis in NASH. A consensus definition and sub‐stages for bridging fibrosis are needed. The severity of perisinusoidal fibrosis should be captured at all stages. Lastly, a method to evaluate features of fibrosis regression should be developed. Conclusion The operating properties of the modifications proposed should be evaluated prospectively to determine reliability and responsiveness.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Standardising the interpretation of liver biopsies in non‐alcoholic fatty liver disease clinical trials

Pai¹,

Kleiner²,

Hart³

et al. 2019

Aliment Pharmacol Ther

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“…12,13 A recent consensus document from the Case Definitions Working Group of the Liver Forum recognized the potential role of quantitation as an entry criterion to drug trials within the field. 14 This study's primary aim was to develop and validate a high-throughput, fully automated, machine learning-based system for the quantitation of all 4 key histologic features contributing to the NASH CRN score, using liver biopsy specimens obtained from patients with NAFLD.…”

Section: Q9mentioning

confidence: 99%

High-Throughput, Machine Learning–Based Quantification of Steatosis, Inflammation, Ballooning, and Fibrosis in Biopsies From Patients With Nonalcoholic Fatty Liver Disease

Forlano¹,

Mullish²,

Γιαννακέας

et al. 2020

Clinical Gastroenterology and Hepatology

107

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Background & Aims Liver biopsy is the reference standard for staging and grading nonalcoholic fatty liver disease (NAFLD), but histologic scoring systems are semiquantitative with marked interobserver and intraobserver variation. We used machine learning to develop fully automated software for quantification of steatosis, inflammation, ballooning, and fibrosis in biopsy specimens from patients with NAFLD and validated the technology in a separate group of patients. Methods We collected data from 246 consecutive patients with biopsy-proven NAFLD and followed up in London from January 2010 through December 2016. Biopsy specimens from the first 100 patients were used to derive the algorithm and biopsy specimens from the following 146 were used to validate it. Biopsy specimens were scored independently by pathologists using the Nonalcoholic Steatohepatitis Clinical Research Network criteria and digitalized. Areas of steatosis, inflammation, ballooning, and fibrosis were annotated on biopsy specimens by 2 hepatobiliary histopathologists to facilitate machine learning. Images of biopsies from the derivation and validation sets then were analyzed by the algorithm to compute percentages of fat, inflammation, ballooning, and fibrosis, as well as the collagen proportionate area, and compared with findings from pathologists’ manual annotations and conventional scoring systems. Results In the derivation group, results from manual annotation and the software had an interclass correlation coefficient (ICC) of 0.97 for steatosis (95% CI, 0.95–0.99; P < .001); ICC of 0.96 for inflammation (95% CI, 0.9–0.98; P < .001); ICC of 0.94 for ballooning (95% CI, 0.87–0.98; P < .001); and ICC of 0.92 for fibrosis (95% CI, 0.88–0.96; P = .001). Percentages of fat, inflammation, ballooning, and the collagen proportionate area from the derivation group were confirmed in the validation cohort. The software identified histologic features of NAFLD with levels of interobserver and intraobserver agreement ranging from 0.95 to 0.99; this value was higher than that of semiquantitative scoring systems, which ranged from 0.58 to 0.88. In a subgroup of paired liver biopsy specimens, quantitative analysis was more sensitive in detecting differences compared with the nonalcoholic steatohepatitis Clinical Research Network scoring system. Conclusions We used machine learning to develop software to rapidly and objectively analyze liver biopsy specimens for histologic features of NAFLD. The results from the software correlate with those from histopathologists, with high levels of interobserver and intraobserver agreement. Findings were validated in a separate group of patients. This tool might be used for objective assessment of response to therapy for NAFLD in practice and clinical trials.

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“…It should also be mentioned that thus far, regulatory authorities consider liver histology (but not NIT) to be the primary endpoint of Phase 3 clinical trials in interim analysis. 11 Finally, histology may become a primary goal in the treatment of NAFLD in the near future as the use of personalized medicine is developed. Treatment of NAFLD with fibrosis and mild activity will require different drugs than very active disease and limited fibrosis.…”

Section: Other Added Values Of Liver Biopsymentioning

confidence: 99%

Diagnosis of non‐alcoholic fatty liver disease/non‐alcoholic steatohepatitis: Why liver biopsy is essential

Bédossa

2018

Liver International

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The pattern of non‐alcoholic fatty liver disease is complex with an association of several lesions, each of them related to different pathophysiological mechanisms. Despite the progress in non‐invasive tools, liver biopsy remains the only diagnostic procedure that can reliably assess these various patterns, their related severity and associations. The most important difficulties of liver biopsy can be avoided if this procedure is performed by an experienced hepatologist and read by a liver pathologist. However, for obvious reasons, biopsy should be restricted to selected patients, especially in the context of clinical trials. Indeed, liver biopsy is considered mandatory by regulatory authorities as a surrogate to assess drug efficacy in Phase 3 clinical trials. In addition to the clinical diagnosis, liver biopsy can be used to score the various histological patterns of disease (NASH‐CRN, SAF scores) and accurately assess the extent of fibrosis, both of which are useful when follow‐up biopsies are performed. When treatment becomes available in the near future, liver biopsy could remain useful for choosing the most suitable therapeutic option based on the main predominant histological features (activity, steatosis, fibrosis).

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Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science

Cited by 153 publications

References 56 publications

Standardising the interpretation of liver biopsies in non‐alcoholic fatty liver disease clinical trials

Standardising the interpretation of liver biopsies in non‐alcoholic fatty liver disease clinical trials

High-Throughput, Machine Learning–Based Quantification of Steatosis, Inflammation, Ballooning, and Fibrosis in Biopsies From Patients With Nonalcoholic Fatty Liver Disease

Diagnosis of non‐alcoholic fatty liver disease/non‐alcoholic steatohepatitis: Why liver biopsy is essential

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