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Effects of Drug-Induced Liver Injury on Hepatology and the Practice of Medicine
3/28/01
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Table of Contents
Effects of Drug-Induced Liver Injury on Hepatology and the Practice of Medicine
Impact of Drug-Induced Liver Injury on the Public
Where Drugs Fit In
The Liver Works Very Well Too Well?
Why Is Rarity a Problem? Hard to study/hard to define
Is anything wrong with approval process?
The Doctor’s Dilemma
Physician’s Information Sources
What Clinicians Face
PPT Slide
Possible solutions
Ways of improving surveillance
DILI Study (pilot phase)
Author: William M. Lee, MD
PPT Slide
DILI Study (phase 2)
Summary
Summary II
Effects of Drug-Induced Liver Injury on Hepatology and the Practice of Medicine
William M. Lee, MD
Department of Internal Medicine
University of Texas Southwestern Medical Center at Dallas
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Impact of Drug-Induced Liver Injury on the Public
● Rare reactions but severe, often fatal
● Little data available re: true incidence
● Who is to blame?
● What do clinicians want?
● What does the public deserve?
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Summary II
Education of physicians is vital
● CME offerings
● Availability of information: Epocrates, Medline
● Other uses of technology possible
● Allows physicians to get back to “Do no harm”
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Where Drugs Fit In
Main thrust of current medical care is prescribing
● 200 billion dollar industry annually
● Pharmacotherapy impacts lives incrementally
● Rare reactions impact lives more dramatically
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Summary
Physicians share responsibility with pharmaceutical companies and FDA for drug reactions
● Clinicians want no trouble (do no harm to themselves)
● But they don’t help by providing the information they themselves need (case reports the exception)
● Improved surveillance will not come from physicians
● Academic physicians have the intrinsic motivation
● Nationwide surveillance system should be considered
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The Liver Works Very Well Too Well?
● We trust the liver implicitly
● Metabolizes many drugs simultaneously
● So we are doubly surprised when it acts up!
● The rarity of drug reactions and their severity is the problem
● Physicians trust the liver as patients do
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Why Is Rarity a Problem? Hard to study/hard to define
● Cannot plan for it
● Cannot recognize it when it comes
● It is catastrophic, like an aneurysm
● Compares to other natural disasters
● But drug-reactions are iatrogenic!
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Is anything wrong with approval process?
● FDA under pressure to approve drugs
● Approval process has been under attack
(7 drugs withdrawn since ‘93)
● Patients apply pressure (for approval) as well
● FDA must serve as gatekeeper/wise father
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The Doctor’s Dilemma
“First, do no harm”
● Be very cautious and not use new drugs
● Be more bold and try new agents without waiting
● Read as much as you can, the data is still not there!
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Physician’s Information Sources
● Medical school/residency teaching
● Practice experience
● PDR
● Drug Ads/Reps
● Reading the literature--case reports!
● News media
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What Clinicians Face
Loss of independence/time & financial pressure
● Much pressure to prescribe new drugs
● No physician can keep up with all rare reactions/interactions (PDR is hard to read)
● Current surveillance system is inadequate
● But physicians rarely contribute to MedWatch!
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PPT Slide
Why post-marketing surveillance fails
● Failure to recognize ‘hepatitis’ as drug-induced
● If drug is stopped, why report?
● Concern about malpractice/adverse outcome
● Withdrawal with increase ALT’s=assumed trivial
● Meant to, just ran out of time/energy/forgot
● Inadequate clinical information/timing/
concomitant drug use/exclusion of other etiologies
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Possible solutions
Do we need legislation to make it happen?
● More stringent drug testing before release
● Active post-marketing surveillance
● Post-marketing studies ?
● More readily accessible drug information
● Better physician post-graduate education
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Ways of improving surveillance
● Monitor actively at academic medical centers
● Monitor through HMO databases
● Continue passive system with incentives
● Revise notification (black box) system
● Technology should help (e.g., Epocrates)
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DILI Study (pilot phase)
Retrospective analysis of 300 cases of severe liver injury (SLI) at 6 academic centers
● Cases accrued through medical records analysis/coding/abnormal lab values
● Case report forms developed
● Criteria for SLI (Bili > 10, INR > 1.5) less strict than for acute liver failure
● Case control format vs. panel of experts
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PPT Slide
Severe Liver Injury Cases
DILI study; n = 230
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DILI Study (phase 2)
Prospective analysis of severe liver injury at a larger number of academic centers
● Provide data on all forms of hepatitis
● Attribution an issue: causality assessment methods are not foolproof
● Would serve as an early warning system
● Limitation: academic centers only
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