Hy's Law

 Briefly, 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.

Clinical trials of the beta blocker dilevalol (enantiomer of labetalol, a diastereoisomeric mixture) showed two such cases in about 1,000 exposures.

The drug was not approved in the United States, and examination of a postmarketing study in Portugal revealed fatal liver injury. 

Clinical trials of tasosartan, an angiotensin II blocking agent, showed a single Hy’s Law case. 

This led to a request for a much larger premarketing database and the drug was abandoned.

Hy’s Law cases represent one end of a spectrum of laboratory abnormalities that indicate liver injury.

 Each of these cases has different sensitivity and specificity as a predictor for the potential for severe liver injury.

 Although it is not possible to provide precise specificity and sensitivity estimates for the various signals, guidance can be provided on use of these major indicators of a potential for severe DILI, as follows:

• An excess of AT elevations to >3xULN compared to a control group
• Marked elevations of AT to 5x-, 10x-, or 20xULN in modest numbers of subjects in the test drug group and not seen (or seen much less frequently) in the control group
• One or more cases of newly elevated total serum bilirubin to >2xULN in a setting of pure hepatocellular injury (no evidence of obstruction, such as elevated ALP typical of gall bladder or bile duct disease, or malignancy, or impaired glucuronidation capacity caused by genetic (Gilbert syndrome) or pharmacologic (treatment with atazanavir or other drugs) factors), with no other explanation (viral hepatitis, alcoholic or autoimmune hepatitis, other hepatotoxic drugs), accompanied by an overall increased incidence of AT elevations >3xULN in the test drug group compared to placebo

Discontinuation of treatment should be considered if:

•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 with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Case Report Forms

Because DILI has resulted in the marketing withdrawal or cessation of development of many drugs, every clinical trial should include case report form pages specifically designed to capture information pertinent to the evaluation of treatment-emergent liver abnormalities.

In addition to collecting information on laboratory abnormalities, clinical symptoms, and the potential cause of any hepatic illness, 

case report forms and narratives should include the following information for cases in which liver injury is found (including control subjects with such injury):

•Time and date from start of drug administration to start of illness.

•Time and date of cessation of drug, or interruption of drug administration.

•Complete description of the injury, including systemic symptoms, other organ involvement, rash, fever, and eosinophilia.

•Outcomes such as death, liver transplant, hospitalization, recovery, and treatment for DILI.

•Free text describing the course of illness, including pertinent physical examination findings, such as hepatomegaly, splenomegaly, right-upper quadrant tenderness, the time course of abnormalities of aminotransferases, ALP, TBL with dates of testing, normal ranges, and results for tests done in addition to those specified in the original protocol, and tests done during any unscheduled visits. These additional laboratory test results, including reference ranges, should also become part of the overall database. Supportive tabular and/or graphical display of serial laboratory data is often desirable in addition to narrative information. Pre-study AT values should be sought, which may suggest chronic liver disease and/or an acute process that may have preceded exposure to the investigational drug.

•Risk factors, especially history of alcohol use; risk factors for NASH such as diabetes, obesity, and hypertriglyceridemia, which may prompt ultrasound examination of the liver to detect steatosis.

•All concomitant drugs (dose, start and stop dates, whether they are known to be hepatotoxic, information on rechallenge or dechallenge with drugs with the same or similar structure).

•Evaluation of nondrug causes: recent hepatitis A, B, and C serology; evidence for biliary obstruction; imaging study results; acute alcoholic hepatitis (recent drinking and AST >2xALT are supportive); recent history of severe hypotension or congestive heart failure; other underlying viral disease.

•All supplemental information, including consultation reports, narrative information, and special studies.

Reference:

https://www.fda.gov/media/116737/download