# Presentation: 661009

## Recognizing Drug-Induced Liver Injury (DILI) in Exposed Populations

***John R. Senior, M.D.***
- Associate Director for Science
- Office of Pharmacoepidemiology and Statistical Science
- Food and Drug Administration (FDA)

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## 
   Material presented here is based on the observations of the speaker for 20 years in academic hepatology and gastroenterology, 5 years as a senior executive in the pharmaceutical industry, 11 years in private consulting to industry, and upon 9.5 years at the FDA: 4.5 years as a medical reviewer for new gastrointestinal drugs, 3 as the Senior Scientific Advisor for hepatology in the Office of Drug Safety, 2 years as Associate Director for Science, Office of Pharmacoepidemiology and Statistical Science. 
   Comments made here do not reflect official policies or positions of the Agency, but are personal opinions of the presenter based on his diverse experiences mentioned.

***   ******Material presented here is based on the observations of the speaker for 20 years in academic hepatology and gastroenterology, 5 years as a senior executive in the pharmaceutical industry, 11 years in private consulting to industry, and upon 9.5 years at the FDA: 4.5 years as a medical reviewer for new gastrointestinal drugs, 3 as the Senior Scientific Advisor for hepatology in the Office of Drug Safety, 2 years as Associate Director for Science, Office of Pharmacoepidemiology and Statistical Science. ***
***   ******Comments made here do not reflect official policies or positions of the Agency, but are personal opinions of the presenter based on his diverse experiences mentioned.***

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## First, Detect it !
 (if you don’t ask or look, you won’t get or find)
 Ask: Is there liver injury or disease?
serum transaminases, other enzymes, bilirubin, INR
  Is it progressive or serious?
progressive = getting worse or likely to do so
serious = disabling, life-threatening, fatal
  Drug-induced or some other cause?
  no pathognomonic test for DILI, including biopsy
  DILI may mimic any known liver disease

*** ******(if you don’t ask or look, you won’t get or find)***
*** ******Ask: Is there ***_***liver***_*** injury or disease?***
***serum transaminases, other enzymes, bilirubin, INR***
***  ******Is it progressive or ***_***serious***_***?***
***progressive = getting worse or likely to do so***
***serious = disabling, life-threatening, fatal***
***  ***_***Drug***_***-induced or some other cause?***
***  ******no pathognomonic test for DILI, including biopsy***
***  ******DILI may mimic any known liver disease***

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## “some other causes”

What are they?
mainly acute hepatitis : viral A or B, seldom C, alcoholic, biliary stones, ischemic, or autoimmune; other causes rarer
How can they be ruled out?
what information should be collected?
What are the odds of other causes?
It’s really a problem of differential diagnosis.

***What are they?***
***mainly acute hepatitis : viral A or B, seldom C, alcoholic, biliary stones, ischemic, or autoimmune; other causes rarer***
***How can they be ruled out?***
***what information should be collected?***
***What are the odds of other causes?***
***It’s really a problem of differential diagnosis.***

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Drug-Induced Liver Injury (DILI)

**Most people exposed to a new drug show no injury;**
**“****tolerators”**
**Some people show transient injury, but adapt;**
**“****adaptors”**
**A few fail to adapt and show serious toxicity !**
**“****susceptibles”**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Drug-Induced Liver Injury (DILI)

**“****tolerators”**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Drug-Induced Liver Injury (DILI)

**“****adaptors”**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Drug-Induced Liver Injury (DILI)

**“****susceptibles”**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

- ... not DILI

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Is It a Bad Drug or Is It aSusceptible Patient?

-   Why do a few people not tolerate it?
-   What’s different about them?
-   Can we find out?
-   A drug tolerated by nearly everybody except     	a very few cannot be considered “toxic.”
***  ******And not give them this drug?***

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Given: Some Drugs are More Toxic

- many or most eliminated in development
- molecular variations in class
- differing potencies of variants
- therapeutic index varies
- variable PK ADME among patients
- variable PD responses in patients
- one dose may (will) not suit all patients

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Relative Hepatotoxicity in Class“- glitazones” (thiazolidenediones)peroxisome proliferator-activated receptor- (PPAR) agents

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Slide 13

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## The Glitazone Family

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Other Drug “Families”

- “-profens”
- benoxaprofen
- flurbiprofen
- ibuprofen
- “-fenacs”
- ibufenac
- bromfenac
- diclofenac

- “-pidems”
- alpidem
- zolpidem
- “-navirs”
- ritonavir
- indinavir
- nefinavir
- saquinavir

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Need research on . . .

- 1)  which cytochrome isoforms attack 	what part of the molecules?
- 2)  which _metabolites_ are more toxic?
- 3)  proof that efficacy and toxicity are in        	different parts of same molecule ?
- 4)  some rules to _predict_ DILI
- 5)  _mechanisms_ causing the DILI
- 6)  not just in animals, but in _humans_

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Should We Be Looking More Carefully at the Patients ?

-   Humans are often very different than animal models
-   They are incredibly diverse genetically
-   They resist being standardized or controlled
-   They take a lot of drugs, diets, supplements, alcohol
-   They have lots of other diseases/disorders/activities
-   The ones treated are not the same as the ones studied
-   They don’t always report troubles promptly

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

##   " Our study is man, as the subject of accidents or diseases. Were he always, inside and outside, cast in  the same mould, instead of differing from his fellow man as much in constitution and in his reaction to stimulus as in feature, we should ere this have reached some settled principles in our art. 

***    ******The practice of medicine is an art, based on science ...  it has not reached, perhaps never will, the dignity of a complete science, with exact laws, like astronomy or engineering.”***** **

- William Osler, M.D. (1849-1919)
- “Teacher and Student,”Minneapolis 1892

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## " ...he who aspires to treat correctly of human regimen must first acquire knowledge and discernment of the nature of man in general – knowledge of its primary constituents and  discernment of the components by which it is controlled.

*"**** ****...he who aspires to treat correctly of human regimen must first acquire knowledge and discernment of the nature of man in general ****–**** knowledge of its primary constituents and  discernment of the components by which it is controlled.*
*... **though they are made from the same materials, no two are alike...”*

-    Hippocrates 460-377 B.C.
-    The Father of Medicine

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Hippocrates 

*** *****“****Nature of Man”***** ***
***       ******elements******	****** qualities******	******   constituents***
***	******fire******	******	******     hot******	******     blood******	***
***	******water******	******	******     wet******	******     phlegm***
***	******air******	******	******     cold******	******     bile - yellow***
***	******earth******	******	******     dry******	******     bile - black***
***  *****“****Airs, Waters, Places”**
**   “****Epidemics”**
**   “****Nutriment”*****	******	***

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Why Are They Susceptible ?

- “idio-sug-krasia” (Hippocrates, ~ 400 B.C.)
**idios (********) - one’s own, self**
**syn (********) - together**
**crasis (********) -  mixing, mixture**
*therefore, *
**a person’s own individual mixture of characteristics, factors; “nature and nurture,” unique in the world**
***[it does NOT mean rare, unexpected, unexplained, although it may or may not be any or all of them]***

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

##  (idiosugkrasia)  

***s.f., (substantive, feminine) ***
**temperament; constitution**

- Pocket Oxford Greek Dictionary
- Oxford University Press, Oxford UK, 2000

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Factors in Idiosyncrasy

-   **genetic, bestowed at conception**
- gender
- cytochromes, enzymes, transport systems
-   **acquired in life since conception**
- age, activities, travels
- infections, immunities, diseases
- diet, obesity, dietary supplements
- other drugs, chemical exposures

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Especially Susceptible Patients

- adverse effect, often not dose-related
- may not be duration-related
- may not depend on prior disease
- unexpected, unpredictable (up to now)
- risk factors not well known
- toxicity often uncommon or rare
***who are they? how can they be identified?***

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Drug Development Issues: Idiosyncratic Drug Toxicity 

-   Occurs despite careful preclinical testing in animals
-   ... and despite careful and costly clinical trials
-   Some problem (perhaps wrong) assumptions:
-   Assuming _drug_ variability is the key to safety
-   Obsolete concepts of “safe and effective” – for all?
-   Assuming one dose/regimen suits all patients
-   Focus on efficacy, little on safety (especially if rare)

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Needles in the Haystack Tyranny of the Numbers - I 

-   *if only 1 patient in 1000 reacts adversely to a drug, should we call the drug “toxic”?*
-   If 1 person in 1000 is idiosyncratically hyper-susceptible to show drug-induced liver injury, how many patients need to be observed to have 95% chance of finding at least 1?

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## A Binomial Answer . . .

- - if i = incidence of a rare event, and u = usual absence of the event, then (i + u) = 1, it happens or it doesn’t. And (i + u)N, where N = number of persons
- - when uN, the chance of seeing _no_ events in a group of N persons, is <0.05, then the chance of seeing at least one is >95%, because 1 – uN = 1- <0.05 = >95%
- - for (0.001 + 0.999)N, need 2995 people to make (0.999)2995 = 0.04996, which is <0.05;
- - **in general, N ******** 3/i for rare events.**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Detection of Rare Safety Problems

- Before approval and marketing
- NDA review: seldom have enough patients, so rare but serious event may not be observed; but if they are seen, investigate!
- After marketing and clinical use
- spontaneous, voluntary reporting useful, but severely underreported and incomplete data
- problems usually worse after marketing

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Liver “Function” Tests

- what are they ?
- what do they mean ?
*Important:  distinguish between liver *_*function*_* and liver *_*injury*_
- they’re the biomarkers we use

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Commonly Used Tests

*enzymes*

- “transaminases”:  ALT
-                              AST

- alkaline phosphatase
- gamma-glutamyl transferase

*substances*

- bilirubin (total, “direct”)
- albumin
- prothrombin (INR)

***injury***

*hepatocellular*
*cholestatic*

-      ***function***
*    **excretory*
*    **synthetic*
*    **synthetic*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Is Serum ALT a Liver Function Test ?

- serum enzymes not just from liver but also from skeletal and heart muscle, gut, etc.
*. . . so let’s not assume “liver”*
- it is _not a function_ or job of the liver to regulate the level of serum enzyme activity
*. . . so let’s not say “function”*
- elevated serum ALT activity *MAY* indicate hepatocellular injury

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Is Serum Transaminase Enough?

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Need Very, Very Specific TestsTyranny of the Numbers - II

- For relatively low prevalence or incidence events, need extremely high specificity of test to avoid “finding” many false positives
- Almost impossible to find a hyper-specific test; compound tests may help: ALT+TBL
- Probably need to add clinical differential diagnostic data and methods to attain

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## 1917-1999 

**Hy Zimmerman**
**1917-1999**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## ESTIMATED CASE FATALITY RATE IN DRUG-INDUCED ACUTE HEPATOCELLULAR INJURYWITH NON-OBSTRUCTIVE JAUNDICE

*Zimmerman. HEPATOTOXICITY, 1978 & 1999*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Intrinsic vs Idiosyncratic Toxicity

- “intrinsic”
- predictable
- dose-related
- similar in animals
- high incidence
- short interval
- types
- directly destructive
- indirect, metabolic
- cholestatic

- “idiosyncratic”
- unpredictable
- not dose-related
- not seen in animals
- low incidence, rare
- variably longer interval
- types
- hypersensitivity
- metabolic
*         ...**H. Zimmerman, 1978*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## HZ...but that’s an oversimplification!“...this dichotomy into intrinsic toxicity or host idiosyncracy is an overly simplified formulation. The potential for injury is arranged along a spectrum, ... modified by several different mechanisms.”

**Relative Importance for Hepatotoxicity**
** ****phosphorus**
**	****	****amanita phalloides**
**	****	****	****carbon tetrachloride**
**	****	****	****	****   ****anabolic steroids**
**tetracycline**
**	****	****	****chlorpromazine**
**	****	****	****	****	****phenytoin**
**	****	****	****	****	****	****	****penicillin**
**Intrinsic Toxicity ------------------------------------*****some of both-*****--------------------------------------  Host Susceptibility**
**___________________________________________________________________________________________**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## “Hy’s Law” ...for drug-induced hepatotoxicity

- If both hepatocellular injury and jaundice occur, look out for at least 10% mortality!
*i.e., when both transaminase and bilirubin elevations occur together.*
-                    *Robert Temple, FDA, 1999*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Searching for Clues, Predictors

- Can ways be found to search pre-approval clinical databases (NDA submissions) for clues or “signals” that predict liver failure in at least some who show the signal?
- Hy Zimmerman was on to a key concept - the combination of an indicator of injury and loss of overall function may be a valid predictor. It needs confirmation.

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## “Temple’s Corollary”       ...for drug-induced hepatotoxicity:Hy’s Law cases arise out of a background of increased incidence of transaminase elevations

- Hy’s Rule-type serious cases of DILI usually arise from a background of increased injury rates, so
- Look for more ALT elevations in those exposed to drug, compared to placebo or control drug*.*
-                    *Robert Temple, FDA, 2004*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

**  **

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## What to Do When a “Signal” Detected

*“**signal” = laboratory abnormality, complaint, finding*
-  immediately (within day or two) confirm by repeat 		tests, examination, questions
-  investigate possible causes AT ONCE ! r/o disease
-  start close observation (3x/week) immediately
-  obtain more information about possible causes
-  obtain consultation as appropriate or needed
-  follow closely (weekly, prn) to normalization or 		worsening and management decision

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## It may be DILI if it’s nothing else

**Diagnosis of exclusion; no test **_**FOR**_** DILI**
**Must gather data to rule out other causes**
**Need to educate “docs” to do it better**
**Develop model for **_**quantitative**_** likelihood estimate**
**Prospective large safety studies needed:**
**for **_**true**_** incidence**
**for risk factors and to design risk management plans**
**for ‘omic’ analyses (gen-, prote-, metabon-) specimens**
**	****for elucidation of mechanisms**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Tip of the Iceberg

**Death or Tx**
**Acute Liver Failure**
**Serious DILI – Threatening**
**Detectable DILI – but Not Serious**
**Patient Adaptation to New Agent Exposure**
**Patients/People Tolerate Exposure Without Effects**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Serious Adverse Events

- Often have relatively low incidence rate, ***i***
- Difficult to establish correct value for ***i***
- Voluntary reporting gives uncertain values
- May be missed in the usual efficacy trials
- Must balance modest clinical benefits for many against serious risks for a few
- Spontaneous reports (AERS) not enough

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Retrospective Database Studies

- Epidemiologic, observational – closer to reality
- A definite improvement on spontaneous reports
- Limited to who was included, data recorded
- No attribution of causality; statistical differences
- Can improve estimates of incidence, risk factors
- But cannot investigate mechanisms or causes or “do it right” in real time, collect specimens

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## How many patients to study?

- Prospective, not retrospective
- Focus on safety, as drug actually prescribed
- Large and long enough to find rare events
- Full accounting,  numbers of cases/exposed
- Use patient self-reporting, then investigate possible cases intensely; get needed info
- Prospective case-control design
- Impartial study conduct: NIH or AHRQ

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Prospective Large Safety Studies

- Offer best chance to learn, and to protect patients
- Need to establish _true incidence_ of DILI
- Need to identify _risk factors_ for rational RM
- Need to investigate _mechanisms_
- In best interests of everybody, including patients, regulators, and sponsors
***In 2005, are we content with safety meaning “not poison,”  and withdrawing “toxic” drugs ?***

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005