Contextual graphics
Michael Merz, MD
Spotfire® User Group Meeting, Basel
Nov 3, 2016
Novartis Institutes for
BioMedical Research
Making narratives smarter
Outline
• Drug-induced liver injury (DILI) as an example
• Key elements for (liver) safety assessment: graphics
and narratives
• Narrative challenges
• Smart narratives
Smart narratives M Merz Nov 3, 2016 2
Drug-induced liver injury (DILI)
• 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
Smart narratives M Merz Nov 3, 2016 3
Major threat to patients, substantial burden for drug development
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»
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
Hy’s law A short introduction
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“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.”
• Reporting requirements and implications
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Hy’s law Reporting requirements and implications
All potential Hy’s law cases have to be
reported as SAE
Major implications in terms of timelines and
content
FDA’s approach to assess liver safety data
The “eDISH” concept
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• Log/log plot of peak (!) ALT and
bilirubin allows efficient
screening of liver safety profiles
• Drill-down to
individual patient
profiles supports
medical assessment
Interactive graphics and text summaries
Drilldown from helicopter to single patient view: from eDISH to...
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...time profiles
...narratives
Comprehensive assessment of suspected cases’ clinical relevance
Exclusion of alternative explanations
Narratives: SAE case summaries
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Structure and content
SAE forms: source data for narratives
Key data domains:
Smart narratives M Merz Nov 3, 2016 9
Data elements and timelines
1. Patient
2. Event
4. Comed
5. Medical history
6. Manufacturer
3. Suspected drug
Narrative example
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A lot of pages to tell a straightforward story
Narrative challenges
Clinical course and labs
Concomitant medication
Tabular summaries
Readability, transparency, frequent updates
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Medical history
Another option: smart narrative
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Automatically updated sparklines and hyperlinked graphs
Executive case summary
• Key points only
Hyperlinks to more detailed graphs
Sparklines to show lab time
course
• All liver tests peak at the same time
• What about GGT?
Graph miniatures for first orientation
• Event occured after dose reduction
• Minor liver abnormalities before event
• No obvious comed effect
B, SoC
A, high dose
A, low dose B, SoC
A, high dose
A, low dose
Patient profiles
Complete, and zoomed in around time of event
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• Event occurs with hep E seroconversion and after viral
RNA occurrence
A, high dose
A, low dose B, SoC
A, high dose
A, low dose
Special narratives: Investigator Notifications
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Presenting data beyond individual case
ALT [x ULN]
TB
IL [
x U
LN
]
Advanced eDISH
Shift plots
What could be next?
• ...Periodic Safety Update Reports (PSURs)?
• ...Meetings?
– preIND
– EoP2
– preNDA
• ...Submissions?
• ...?
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Smart...
Conclusions
• Narratives are a key element of drug safety reporting
• Challenges are comprehensive and complex content,
as well as the need for repeated updates during
drafting stage
• Providing a case summary, along with interactive
graphical elements (“smart narrative”) may significantly
improve efficiency, readability and transparency
• A similar concept, i.e. sharing data with regulators using
interactive graphics, may be applicable to other
documents and processes
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