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Clinical Trial
. 2020 Dec;73(6):1322-1332.
doi: 10.1016/j.jhep.2020.06.025. Epub 2020 Jun 28.

Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials

Beth A Davison  1 , Stephen A Harrison  2 , Gad Cotter  3 , Naim Alkhouri  4 , Arun Sanyal  5 , Christopher Edwards  3 , Jerry R Colca  6 , Julie Iwashita  6 , Gary G Koch  7 , Howard C Dittrich  6
Affiliations
Clinical Trial

Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials

Beth A Davison et al. J Hepatol. 2020 Dec.

Abstract

Background & aims: Liver biopsies are a critical component of pivotal studies in non-alcoholic steatohepatitis (NASH), constituting inclusion criteria, risk stratification factors and endpoints. We evaluated the reliability of NASH Clinical Research Network scoring of liver biopsies in a NASH clinical trial.

Methods: Digitized slides of 678 biopsies from 339 patients with paired biopsies randomized into the EMMINENCE study - examining a novel insulin sensitizer (MSDC-0602K) in NASH - were read independently by 3 hepatopathologists blinded to treatment code and scored using the NASH CRN histological scoring system. Various endpoints were computed from these scores.

Results: Inter-reader linearly weighted kappas were 0.609, 0.484, 0.328, and 0.517 for steatosis, fibrosis, lobular inflammation, and ballooning, respectively. Inter-reader unweighted kappas were 0.400 for the diagnosis of NASH, 0.396 for NASH resolution without worsening fibrosis, and 0.366 for fibrosis improvement without worsening NASH. In the current study, 46.3% of the patients included in the study based on 1 hepatopathologist's qualifying reading were deemed not to meet the study's histologic inclusion criteria by at least 1 of the 3 hepatopathologists. The MSDC-0602K treatment effect was lowest for those histologic features with lower inter-reader reliability. Simulations show that the lack of reliability of endpoints and inclusion criteria can drastically reduce study power - from >90% in a well-powered study to as low as 40%.

Conclusions: The reliability of hepatopathologists' liver biopsy evaluation using currently accepted criteria is suboptimal. This lack of reliability may affect NASH pivotal studies by introducing patients who do not meet NASH study entry criteria, misclassifying fibrosis subgroups, and attenuating apparent treatment effects.

Lay summary: Since liver biopsy analysis plays such an important role in clinical studies of non-alcoholic steatohepatitis, it is important to understand the reliability of hepato-pathologist readings. We examined both inter- and intra-reader variability in a large data set of paired liver biopsies from a clinical trial. We found very poor inter-reader and modest intra-reader variability. This result has important implications for entry criteria, fibrosis stratification, and the ability to measure a treatment effect in clinical trials.

Keywords: Diabetes Mellitus; Histology; Insulin Resistance; Non-alcoholic fatty liver disease; Type 2; Validation studies.

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Conflict of interest statement

Conflict of interest Beth Davison, Gad Cotter, and Christopher Edwards report grants from Cirius Therapeutics, Inc. during the study's conduct. Stephen Harrison reports grants from Cirius Therapeutics, during the conduct of the study; grants, personal fees and other from Galectin, Genfit, Madrigal, Metacrine, NGM Bio, grants and personal fees from 3VBio, Axcella, Cirius Therapeutics, Contravir, CymaBay, Galmed, Gilead, BMS, Hightide, Intercept, Immuron, Novartis, Novo Nordisk, Pfizer, Second Genome, Tobira/Allergan, grants and other from NorthSea, grants from Conatus, personal fees and other from Akero, Altimmune, Blade Therapeutics, personal fees from CiVi Biopharma, Echosens, Gelesis, CLDF, Consynance, Corcept, HistoIndex, Indalo, Innovate, IQVIA, Lipocine, Medpace, Perspectum, Prometheus, Poxel, Prometic, Fortress Bio, Terns, Viking, outside the submitted work. Naim Alkhouri reports grants from Cirius Therapeutics during the conduct of the study; and grants from Albireo, Ackero, Boehringer Ingelheim, Bristol-Myers Squibb, Galmed, Genfit, Hanmi, Inventiva, Madrigal, MedImmune, Novartis, Novo Nordisk, Pfizer, Poxel, and Zydus; grants and personal fees from Allergan, Gilead, Intercept; AbbVie, Alexion and Eisai and personal fees from Exelixis and Salix outside the submitted work. Arun Sanyal reports grants from Echosens-Sandhill, Bristol-Myers Squibb, Sequana, Tiziana; grants and other from Genfit, Mallinckrodt, Pfizer; non-financial support and other from Immuron; other from Sanyal Bio, Exhalenz, Conatus, Akarna, Elsevier, Intercept, Salix, UptoDate, Boehringer Ingelhiem, Novartis, Nimbus, Galectin, Merck, Hemoshear, Lilly, Novo Nordisk, Fractyl, Durect, Indalo, Allergan, Chemomab, Affimmune, Teva, Ardelyx, Terns, ENYO, Birdrock, Albireo, Sanofi, Jannsen, Takeda, Zydus, BASF, Amra, Perspectum, OWL, Poxel, Servier, Second Genome, General Electric, and 89 Bio outside the submitted work. Jerry Colca and Howard Dittrich report personal fees from Cirius Therapeutics, Inc, during the conduct of the study. In addition, they have a patent MSDC-0602K method of use pending. Julie Iwashita reports personal fees from Cirius Therapeutics, Inc. during the conduct of the study. Gary Koch is the principal investigator of a biostatistical agreement between Momentum Research, Inc. and the University of North Carolina at Chapel Hill, and that agreement provided the structure for his activity for this article. He is also the principal investigator of many such biostatistical agreements with other biopharmaceutical sponsors, including AbbVie, Amgen, Arena, AstraZeneca, Eli Lilly & Co., Forest Research Institute (Allergan), GlaxoSmithKline, Merck, Novartis, Otsuka, Pfizer, and Sanofi, although his activities for those sponsors are not related to the content of this article. Information concerning all biostatistical agreements for which Gary Koch is the principal investigator is publicly available through the University of North Carolina at Chapel Hill. Please refer to the accompanying ICMJE disclosure forms for further details.

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