Michael Merz, Novartis Institutes for BioMedical Research
Spotfire® User Group Meeting, Foster City, Oct 4, 2016
Visual thinking in drug safety Learning from the FDA
3D plot
Outline
Visual thinking in drug safety | M Merz | October 4, 2016
Drug-induced liver injury (DILI): background and challenges
DILI assessment: standard industry approaches and FDA approach
Suggested improvements/expansions to current process
2
Drug-induced liver injury (DILI): key troublemaker
Visual thinking in drug safety | M Merz | October 4, 2016 3
Major threat to patients, substantial burden for drug development
Leading cause of acute liver failure in the US
3% fatal outcome, 5% need for transplantation
Most frequent reason for drug withdrawals
Substantially reduces treatment options for patients
Significantly contributes to attrition in development
Major challenge: lack of suitable biomarkers
1984
Methaqualon
1991
Triazolam
2004
Rofecoxib
1962
Thalidomide
Terfenadine
Fenfluramine
Alosetron
Cisapride
Cerivastatin
1970
Ibufenac
2001
Trovafloxacin
1998
Bromfenac
1997
Tolcapone
Tolrestat
2000
Troglitazone
Amineptine
2006
Ximelagatran
2003
Nefazodone
1959
Iproniazid
1967
Oxyphenisatin
1982
Benoxaprofen
Ticrynafen
1985
Perhexiline
1996
Alpidem
2005
Pemoline
2007
Lumiracoxib
W i t h d r a w a l s
Tolcapone Nefazodone
Nevirapine Naltrexone
Amiodarone
Methotrexate Tolvaptan
Bosentan
Ambrisentan
Ketoconazole Felbamate
Gemtuzumab
Idarubicin
Isoniazid
Pemoline
Dantrolene Epirubicin
Adefovir
Docetaxel
Flutamide
Reasons for withdrawals
Drug Info J 2001; 35:293 «Pre-Hy’s Law» «Post-Hy’s Law»
Hy’s law
Visual thinking in drug safety | M Merz | October 4, 2016 4
A short introduction
“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.”
Definition
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
Tables vs graphics Data reduction vs understanding
Visual thinking in drug safety | M Merz | October 4, 2016 5
Active Control Active Active
Study 1 Study 2 Pooled data
Static vs interactive graphs Drilldown from helicopter to single patient view: from eDISH to...
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...time profiles
...narratives
Straightforward assessment of suspected cases’ clinical relevance
Exclusion of alternative explanations
ALT [x ULN]
TB
IL [
x U
LN
]
Improvements (1): Splitting treatments by Trellis panels
Visual thinking in drug safety | M Merz | October 4, 2016
eDISH plot by pooled active vs control treatment
Potential Hy‘s law cases spotted easily
Only limited assessment of relevance of individual cases feasible
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ALT [x ULN]
TB
IL [
x U
LN
] Improvements (2): Adding sequence, time interval, and ALP
Visual thinking in drug safety | M Merz | October 4, 2016
Modifications take into account key information on sequence of events, time interval, and pathology
Specifically useful when larger numbers of potential Hy‘s law cases are expected (oncology, hepatitis)
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Color by peak sequence, size by 1/time interval, shape by R flag
Definition of normal range accounting for bivariate distribution
mDISH: using change from baseline instead of multiples of ULN
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Improvements (3): bivariate NR, multiples of baseline Accounting for correlated variables and baseline differences
eDISH vs mDISH in practice
Visual thinking in drug safety | M Merz | October 4, 2016
Using multiples of baseline reduces false positives
mDISH accounts for different baselines across different patient populations
Color coding by gender
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ALT [x ULN] ALT [x bsl]
TB
IL [
x U
LN
]
TB
IL [
x b
sl]
Visual thinking in drug safety | M Merz | October 4, 2016
Change from baseline beyond mDISH Color coding by parameter
Dose-and time-dependent effect on ALT levels, no apparent effect on bilirubin levels
Easily interpretable integration of dose and time information across variables, displaying all individual data
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Visual thinking in drug safety | M Merz | October 4, 2016
Liver test panel profiles over time by patient Treatment end indicated by vertical red line
Parallel ALT and AST peaks, ALT more pronounced
No apparent effect on bilirubin levels
Signs of adaptation: reversible ALT peaks despite continued treatment
12
Drill-down to individual patient profiles (ex 1) Synoptic plot of ALT, comeds, and AEs over time
Visual thinking in drug safety | M Merz | October 4, 2016
Acetaminophen intake prior to ALT peak
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Visual thinking in drug safety | M Merz | October 4, 2016
Headache prior to ALT peaks: acetaminophen intake?
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Drill-down to individual patient profiles (ex 2) Synoptic plot of ALT, comeds, and AEs over time
Expanding dataspace: SAFE-T’s new liver safety biomarkers
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Supporting early detection, prognosis, and mechanistic understanding
Nine new liver safety biomarkers supported by EMA and/or FDA for exploratory use in clinical drug development:
Marker Application
Total HMGB1 Mechanism (necrosis), prognosis
Hyperacetylated HMGB1 Mechanism (immune activation), prognosis
Osteopontin Prognosis
Total Keratin 18 Mechanism (necrosis), prognosis
Caspase-cleaved keratin 18 Mechanism (apoptosis), prognosis
MCSFR1 Mechanism (immune activation), prognosis
miR-122 Detection, mechanism (hepatocyte leakage)
GLDH Detection, mechanism (mitochondrial injury)
SDH Detection
To account for rich, multivariate data, proper visualization and analysis are needed
Conclusions
Visual thinking in drug safety | M Merz | October 4, 2016 16
Drug-Induced Liver Injury (DILI) is a major threat to patients, and a substantial burden for drug development
Key challenge is the lack of suitably sensitive, specific, and predictive biomarkers
Current key markers work in a two-dimensional dataspace, looking at liver cell integrity and function
Standard approach to liver safety assessment in industry is still often via tabular summaries and patient listings
FDA has introduced a graphical approach to liver safety assessment (»eDISH»), utilizing interactive graphics in a custom-made software tool
The tool is very efficient, but may benefit from some improvements
Future approaches will have to account for additional markers, essentially switching from bivariate to multivariate assessment methods
Tools to support such methods do not have to be built from scratch, but can easily be implemented in off-the-shelf software such as TIBCO SpotfireTM
Visual thinking in drug safety | M Merz | October 4, 2016 17
Thank You!!