Contextual graphics. Making narratives smarter. Michael Merz, MD Spotfire User Group Meeting, Basel Nov 3, 2016

Transcription

1 Novartis Institutes for BioMedical Research Contextual graphics Making narratives smarter Michael Merz, MD Spotfire User Group Meeting, Basel Nov 3, 2016

2 Outline Drug-induced liver injury (DILI) as an example Key elements for (liver) safety assessment: graphics and narratives Narrative challenges Smart narratives 2

3 Drug-induced liver injury (DILI) Major threat to patients, substantial burden for drug development W i t h d r a w a l s 1959 Iproniazid 1962 Thalidomide Reasons for withdrawals 1970 Ibufenac 1967 Oxyphenisatin 1982 Benoxaprofen Ticrynafen 1985 Perhexiline 1984 Methaqualon 1991 Triazolam 1996 Alpidem 1997 Tolcapone Tolrestat Fenfluramine 1998 Bromfenac Terfenadine Docetaxel Nefazodone Tolcapone Nevirapine Amiodarone Adefovir Naltrexone Methotrexate Tolvaptan Bosentan Idarubicin Ketoconazole Felbamate Gemtuzumab Isoniazid Pemoline Ambrisentan Epirubicin Flutamide Dantrolene 2000 Troglitazone Amineptine Alosetron Cisapride 2004 Rofecoxib 2003 Nefazodone 2001 Trovafloxacin Cerivastatin 2006 Ximelagatran 2005 Pemoline 2007 Lumiracoxib Drug Info J 2001; 35:293 «Pre-Hy s Law» «Post-Hy s Law» 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 3

4 Hy s law A short introduction 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 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. 4

5 Hy s law Reporting requirements and implications Reporting requirements and implications All potential Hy s law cases have to be reported as SAE Major implications in terms of timelines and content 5

6 FDA s approach to assess liver safety data The edish concept Log/log plot of peak (!) ALT and bilirubin allows efficient screening of liver safety profiles Drill-down to individual patient profiles supports medical assessment 6

7 Interactive graphics and text summaries Drilldown from helicopter to single patient view: from edish to......time profiles...narratives Comprehensive assessment of suspected cases clinical relevance Exclusion of alternative explanations 7

8 Narratives: SAE case summaries Structure and content 8

9 SAE forms: source data for narratives Data elements and timelines Key data domains: 1. Patient 2. Event 3. Suspected drug 4. Comed 5. Medical history 6. Manufacturer 9

10 Narrative example A lot of pages to tell a straightforward story 10

11 Narrative challenges Readability, transparency, frequent updates Clinical course and labs Medical history Concomitant medication Tabular summaries 11

12 Another option: smart narrative Automatically updated sparklines and hyperlinked graphs Executive case summary Key points only Sparklines to show lab time course All liver tests peak at the same time What about GGT? Hyperlinks to more detailed graphs Graph miniatures for first orientation 12

13 Patient profiles Complete, and zoomed in around time of event B, SoC A, high dose A, low dose A, high dose B, SoC A, low dose A, high dose A, low dose A, low dose A, high dose B, SoC Event occured after dose reduction Minor liver abnormalities before event No obvious comed effect Event occurs with hep E seroconversion and after viral RNA occurrence 13

14 TBIL [x ULN] Special narratives: Investigator Notifications Presenting data beyond individual case Advanced edish Shift plots ALT [x ULN] 14

15 What could be next? Smart......Periodic Safety Update Reports (PSURs)?...Meetings? preind EoP2 prenda...submissions?...? 15

16 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 16