Contextual graphics - PerkinElmergraphical elements (“smart narrative”) may significantly improve efficiency, readability and transparency •A similar concept, i.e. sharing data

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:

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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?

• ...?

Smart narratives M Merz Nov 3, 2016 15

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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