Histology Series Session 5: Causality Assessment and the Role of Liver Biopsy as Part of the Evaluation of Suspected DILI in NASH Clinical Trials

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January 28, 2022

Causality assessment for suspected drug-induced liver injury (DILI) is a major challenge during drug development and becomes a greater challenge when studies are done in patients with NASH who typically enter the trial already with liver blood test elevations.

Whether or not to obtain a liver biopsy to aid in diagnosis of suspected DILI is a subject of ongoing debate. The inherent risks of a liver biopsy must be weighed against the potential useful information to be obtained from evaluation of liver tissue. Histologic results may be nonspecific and have little impact in establishing the diagnosis of DILI or in changing the clinical assessment; however, histologic evaluation of liver tissue is the only way to characterize the pattern, severity, and distribution of hepatic injury, and may have prognostic value.

Prior to considering a liver biopsy, other issues must be addressed, such as the extent and nature of blood tests to obtain, the phase of drug development, and the issue of rechallenge. Also, consideration as to the establishment of an external DILI monitoring committee prior to study start, were discussed. 


The goals of this session were to address:  

  1. The pros and cons of obtaining a liver biopsy as part of the evaluation of new onset of elevated liver blood tests occurring during NASH clinical trials.   
  2. What information may be obtained from the histologic read that could assist in causality assessment.  
  3. Defining the spectrum of histology that can be seen with NASH to differentiate finding of NASH versus findings of DILI.  
  4. Best practices for assessment of unexpected or atypical findings found on histology.  
  5. What work-up (e.g., hepatitis E) should occur prior to obtaining a liver biopsy to assist in causality assessment.  
  6. Monitoring and stopping rules for DILI assessment.  
  7. The Phase of NASH drug development and extent of assessment.  
  8. The establishment of an external DILI monitoring committee prior to initiation of study. 
Materials

Agenda

Presentations

Setting the Stage: Review of Issues and Recent Data

Melissa Palmer, Liver Consulting LLC

Case Examples of DILI Superimposed on NASH

David Kleiner, National Cancer Institute, NIH