Drug-Induced Liver Injury: Premarketing Clinical Evaluation

Status: Final

Date: July 2009

Target Audience:

Industry sponsors and investigators involved with drug development studies focused on identifying drug-induced liver injury (DILI)


For drugs that have been approved and later withdrawn from the market due to reports of severe liver damage (hepatotoxicity). Some of the damage can be reversed; however, there are rare events where hepatotoxicity is irreversible. Although there are methods for detecting liver damage, it would be more helpful to identify the potential for liver damage earlier in drug development.


Some individuals are susceptible to DILI, while others are not. When researchers looked at previously-collected data, they noticed specific signs of liver damage, such as higher aminotransferase (AT) levels (an enzyme helpful for bilirubin excretion, a process in which the liver excretes bile). Damage to liver cells (hepatocellular injury) is associated with high AT levels, specifically alanine aminotransferase (ALT) and aspartate aminotransferase (AST). However, high AT levels by themselves are not considered precursors of DILI. Rather, high AT levels and impaired bilirubin excretion that cannot be explained by other causes (eg, hepatitis) is an indication that a drug has potential to cause DILI. This observation is known as Hy’s law.

An investigator conducting a clinical trial can use the following criteria as potential indicators for DILIs:

  1. Treatment group has higher AT levels than the control group (>3x the upper limit for normal, or ULN).
  2. More subjects in the treatment group have 5x-20xULN, while subjects in the control group do not.
  3. One or more instances of high total serum bilirubin levels (>2xULN) plus hepatocellular injury with no obvious cause (eg, gall bladder, hepatitis) and criterion #1.

These criteria are not always indicators of DILI; for example, aspirin can produce higher AT levels >3ULN.


For investigators conducting clinical trials, the guidance suggests the following:

  1. Subjects with stable pre-existing liver disease intended to be included in the later phases of clinical trials should be thoroughly screened first to ensure that liver function (eg, bilirubin) is not impaired.
  2. Periodically monitor subjects for abnormal liver symptoms (nausea, fatigue, fever, discomfort in upper right abdomen) as these may appear before the diagnostic tests identify abnormal levels of liver enzymes. Monitor subjects more frequently (including repeat tests) if the clinical trials are shorter or show results that suggest abnormal liver function.
  3. If an investigator suspects the abnormal test results may be possible DILI, the investigator should monitor the subject closely, gathering additional information that would help rule out other possible causes of the liver injury (eg, hepatitis, alcohol use, concomitant medications, cardiovascular diseases). If closer monitoring includes assessments not listed in the protocol, the investigator should document this information in the case report and continue monitoring the subject until normal test results occur.
  4. An investigator can discontinue drug administration while continuing to monitor the subject based on the following FDA guidelines:
  • ALT or AST>8xULN
  • ALT or AST>5xULN for more than 2 weeks
  • ALT or AST>3xULN and (TBL>2xULN or INR>1.5)
  • ALT or AST>3xULN plus abnormal liver symptoms

The decision to withdraw study drug, wait, then administer study drug again (rechallenge) depends on a risk/benefit consideration conducted by an institutional review board.
Notify the FDA of any suspected adverse event that follows Hy’s law, even if subsequent assessment identifies another cause.
The FDA includes a recommended list of liver function tests, analyses, and means of documenting information during clinical trials that may help identify DILIs.


This guidance is useful for investigators attempting to identify signals indicative of DILI earlier in drug development, potentially avoiding the situation of having an approved drug removed from the market because of DILI. What is more interesting, though, is the research stimulated by the FDA’s Critical Path Initiative that is attempting to identify biomarkers and other factors that would help predict what types of individuals would be susceptible to DILI. Initial results appear promising; however, more research is needed.

For more information on this issue, contact the Kulkarni Law Firm.