3d plot - perkinelmer€¦ · 3d plot. outline visual thinking in drug safety | m merz | october 4,...

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


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


Active Control Active Active

Study 1 Study 2 Pooled data

Static vs interactive graphs Drilldown from helicopter to single patient view: from eDISH to...


...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


eDISH plot by pooled active vs control treatment

Potential Hy‘s law cases spotted easily

Only limited assessment of relevance of individual cases feasible

7

ALT [x ULN]

TB

IL [

x U

LN

] Improvements (2): Adding sequence, time interval, and ALP


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)

8

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


Improvements (3): bivariate NR, multiples of baseline Accounting for correlated variables and baseline differences

eDISH vs mDISH in practice


Using multiples of baseline reduces false positives

mDISH accounts for different baselines across different patient populations

Color coding by gender

10

ALT [x ULN] ALT [x bsl]

TB

IL [

x U

LN

]

TB

IL [

x b

sl]


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

11


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


Acetaminophen intake prior to ALT peak

13


Headache prior to ALT peaks: acetaminophen intake?

14

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


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


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


Thank You!!

3d plot - perkinelmer€¦ · 3d plot. outline visual thinking in drug safety | m merz | october 4,...

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