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Hy’s Law and eDISH for Clinical Studies

  • John SeniorEmail author
  • Ted Guo
Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

We present in this review a brief background of innovative concepts underlying the expression of Hy’s law and the diagnostic eDISH program. The term Hy’s law is a sobriquet stated by Robert Temple in April 1999, with Dr. Hyman Zimmerman present but modestly objecting. Subsequently John Senior and Ted Guo in the Food and Drug Administration (FDA) Office of Pharmacoepidemiology and Statistical Sciences (OPaSS) together developed in 2003–2004 a graphic program called eDISH, acronym for evaluation of Drug-Induced Serious Hepatotoxicity in clinical trial subjects. It aimed at facilitating diagnosis of the probable cause of significant serum liver test abnormalities. Step one was to look at all values over time of serum alanine aminotransferase (ALT) and total bilirubin (TBL) in all subjects in a trial, and display peak values of both ALT and TBL for each subject in an x-y plot to assess incidence by severity. Step two was a time course plot and clinical narrative to diagnose whether subjects of interest with more severe changes of both peak ALT and TBL were caused by the drug, at least probably, meaning more likely than by all other possible causes combined. The eDISH program was intended for use in clinical trials by FDA medical reviewers, but has been copied and widely misunderstood. The first step ALTxTBL plot does NOT define a Hy’s law case; to do so requires making a medical differential diagnosis of probable drug cause. The eDISH program is NOT simply a graph of serum chemistry elevations.

Key words

Serum enzyme activities Serum bilirubin concentration Causality diagnosis Time course Clinical narrative 

Abbreviations

AASLD

American Association for the Study of Liver Diseases

ALT

Alanine aminotransferase = serum glutamic-pyruvic transaminase, SGPT

AST

Aspartate aminotransferase = serum glutamic-oxaloacetic transaminase, SGOT

CDER

Center for Drug Evaluation and Research (FDA)

CIOMS

Council for International Organization of Medical Science

DILI

Drug-induced liver injury

eDISH

evaluation of drug-induced serious hepatotoxicity

FDA

Food and Drug Administration

NAD+

Oxidized form of nicotinamide adenine dinucleotide = old name DPN, diphosphpyridine nucleotide (oxidized form)

NADH

Reduced nicotinamide adenine dinucleotide = old name DPNH2, diphosphpyridine nucleotide (reduced form)

NE, NW, SE, SW

Quadrants of an eDISH first plot (North = Upper, East = right, South = lower; W = left

NIH

National Institutes of Health

OPaSS

Office of Pharmacoepidemiology and Statistical Science

OTS

Office of Translational Sciences

RUCAM

Roussel-Uclaf Causality Assessment Method

TBL

Serum total bilirubin

ULN

Upper limit of normal

Notes

Disclaimer

The views expressed are those of the authors and do not necessarily represent the position of nor imply endorsement from the U. S. Food and Drug Administration of the United States’ Government.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Office of Surveillance and Epidemiology, Center for Drug Evaluation and ResearchU.S. Food and Drug AdministrationSilver SpringUSA
  2. 2.Office of Biostatistics, Office of Translational Sciences, Center for Drug Evaluation and ResearchU.S. Food and Drug AdministrationSilver SpringUSA

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