For clinical laboratory data analyses, statistical tabulations are typically generated to list the number of subjects in each treatment group with ALT, AST, TBL with n times of ULN (upper limit of normal (range)). For AST and ALT, n=3 and for TBL, n=2.
ALT, AST, TBL are all “liver enzymes” and are liver function test parameters. Other liver test parameters may also include GGTP and ALP, and others.
- ALT (alanine aminotransferase or SGPT)
- AST( aspartate transaminase or SGOT),
- TBL (total bilirubin)
- GGTP (gamma-glutamyl transpeptidase)
- ALP (alkaline phosphatase)
In clincal trials, liver test parameters are the basis for assessing the so-called DILI (drug-induced liver injury).
Acording to FDA’s guidance “ Drug-Induced Liver Injury: Premarketing Clinical Evaluation“, when assessing the DILI, Hy’s law can be followed. Hy’s law is based on the work by Hy Zimmerman, a major scholar of drug-induced liver injury.
Hy’s Law cases have the following three components:
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control drug or placebo
2. Among trial subjects showing such AT elevations, often with ATs much greater than 3xULN, one or more also show elevation of serum TBL to >2xULN, without initial findings of cholestasis (elevated serum ALP)
3. No other reason can be found to explain the combination of increased AT and TBL, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of causing the observed injury
Finding one Hy’s Law case in the clinical trial database is worrisome; finding two is considered highly predictive that the drug has the potential to cause severe DILI when given to a larger population.
Hy’s law and DILI assessment is also specifically mentioned in FDA CDER Review Template “Clinical Safety Review of an NDA or BLA”
At present, it appears that a potential for severe hepatotoxicity may be signaled by a set of findings sometimes called Hy’s Law, based on the observation by Hy Zimmerman, a major scholar of drug-induced liver injury (DILI), that a pure hepatocellular injury leading to jaundice had serious implications, a 10 to 50 percent mortality. Any Hy’s Law cases should be identified in the treatment group (e.g., subjects with any elevated aminotransferase (AT) of >3x upper limit of normal (ULN), alkaline phosphotase (ALP) >2xULN, and associated with an increase in bilirubin ≥2xULN).
My colleague used to argue with me about the use of 3 times x ULN for ALT and AST and cited the NCI’s CTC (common toxicity criteria) as the evidence. In NCI’s Common Toxicity Criteria, the 2.5 x ULN elevation of ALT and AST would be considered as adverse event with Grade 2 (corresponding to moderate AE severity). However, the NCI has shifted the Common Toxicity Criteria to CTCAE (Common Terminology Criteria for Adverse Events). In CTCAE, AST, ALT is consistent with the FDA guidance (i.e., 3xULN would be considered as grade 2)
Recently, FDA, industry and academia contemplate a new approach to gauging drug induced liver injury by using individual patients’ baseline (instead of ULN) liver enzyme measurements, a move that some say could eliminate problems with the use of the upper limit of normal (ULN) and allow for the assessment of DILI in cases where there is underlying liver injury.
- Drug-Induced Liver Injury (DILI) – FDA CLINICAL INVESTIGATOR TRAINING COURSE
- Drug-Induced Liver Injury: Making Decisions, Making Progress by Dr throckmorton
- Issues and Controversies in DULI
- Drug Induced Liver Injury (DILI)
- Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
- Zimmerman, HJ, 1999, Drug-Induced Liver Disease
- Dr Avigan, Drug-Induced Liver Injury – Epidemilogy & Considerations of Risk
- Dr Temple, Does Pre-Existing Liver Disease Make DILI More Likely?