CDISC 2020 China Interchange

CDISC 2020 China InterchangeA Virtual Event | 5-7 August 2020

Disclaimer and Disclosures

• The views and opinions expressed in this presentation are those of the author and do not necessarily reflect the official policy or position of CDISC.

2CDISC 2020 China Interchange | #CDISCChina #ClearDataClearImpact

Integrating New Technology for CDISC (Graph Database) with FAERS and ESRI to Transform Clinical Data Analytics Presented by Vidya MuthukumarSenior Data Analyst, Project Programming, IQVIA Biotech, IQVIA

5-7 August 2020

Agenda

1. FDA Adverse Event Reporting System (FAERS)2. DILI and Hy’s Law3. Graph Database and FAERS data based on DILI4. Clinical data integration with ArcGIS5. Clinical Data Analytics

Graph Database and FDA Adverse Event Reporting System (FAERS)

FAERS database

Hy’s Law and Drug-Induced Liver Injury (DILI)

FDA Adverse Event Reporting System (FAERS)

There have been many studies on Drug-Induced Liver Injury (DILI) Classification

using US FDA Approved Drug Labeling and (FAERS) data.

Many drugs have either been discontinued from clinical trials or withdrawn after

being approved because of hepatic adverse effects (Maddrey 2005) & (Senior 2007).

Some of these AEs can be serious as evidenced by drug-induced liver injury (DILI).

They have been listed as the leading cause of acute liver failure in the US. DILI has

become one of the most important concerns in drug development and approval

process (Kaplowitz 2001).

6CDISC 2020 China Interchange | #CDISCChina #ClearDataClearImpactSource: www.fda.gov/data/faers


Hy’s Law and Drug-Induced Liver Injury (DILI) Hy’s Law: Hy's law is a rule that

states that a patient is at high risk of a fatal drug-induced liver injury (DILI) if given a medication that causes hepatocellular injury with jaundice.

DILI: Drug-induced liver injury (DILI; also known as drug-induced hepatotoxicity) is caused by medications (prescription or OTC), herbal and dietary supplements (HDS), or other xenobiotics that result in abnormalities in liver tests or in hepatic dysfunction that cannot be explained by other causes.

Source: www.FDA.gov


FDA’s guidance: “ Drug-Induced Liver Injury: Premarketing Clinical Evaluation“, when assessing the DILI, Hy’s law can be followed. Hy’s law is based on the work by Hy Zimmerman, a scholar of drug-induced liver injury. Hy’s Law cases have the following three components: 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.

Hy’s Law and Drug-Induced Liver Injury (DILI)

Source: www.FDA.gov

9CDISC 2020 China Interchange | #CDISCChina #ClearDataClearImpactSource: www.Nature.com

Hy’s Law in Lab Test Results


For clinical laboratory data analyses, statistical tabulations are typically generated to

list the number of subjects in each treatment group with ALT, AST, TBL with n times of

ULN (upper limit of normal (range)). For AST and ALT, n=3 and for TBL, n=2.

ALT, AST, TBL are all “liver enzymes” and are liver function test parameters.

ALT (alanine aminotransferase or SGPT) AST(aspartate transaminase or SGOT), TBL (total bilirubin) ALP (alkaline phosphatase)

Source: www.FDA.gov

Clinical Data and GIS Mapping


Worldwide Causes of Acute Liver Failure

Source: www.nejm.org/

Graph Database and FDA Adverse Event Reporting System (FAERS)

FAERS database

Neo4j Life Sciences and Healthcare Network

Graph Database To Visualize Clinical DataNeo4j to store and visualize clinical data

13CDISC 2020 China Interchange | #CDISCChina #ClearDataClearImpactSource: www.neo4j.com/

Graph Database To Visualize Clinical Data for DILI


Graph Database to Visualize Clinical Data for DILI


Clinical Data Analytics

Liver Enzymes Lab Test Results using FDA’s Hy’s Law and DILI


Clinical Data and eDISH

Hy’s Law principle formed the basis for the FDA’s development of a software program called “eDISH” (for Evaluation of Drug-Induced Serious Hepatotoxicity). It allowed analysis of clinical trials data for hepatocellular injury by serum alanine aminotransferase (ALT) activity and of whole liver dysfunction by total bilirubin (TBL) concentration. This data was measured in clinical trials, according to protocol. For eDISH analysis, data from case reports for subjects enrolled in a trial were surveyed for peak values of ALT and TBL over their entire period of observation

DILI in an FDA submission

No CDISC submission

DILI analysis as part of safety

Deliverables

eDISH peak ALT/AST - peak TBL plot

Listing showing Lab-values over time

Patient narratives

Source: www.FDA.gov

Hy’s Law in Lab Test Results


Hy’s Law in Lab Test Results for Clinical Analytics


Conclusion

DILI and Regulatory Concerns

Handling Liver Test Evaluations

DILI Risk and Regulatory Concerns

21CDISC 2020 China Interchange | #CDISCChina #ClearDataClearImpactSource: www.FDA.gov

Study Sponsors should ensure their investigators report any liver test elevations immediately.

If DILI confirmed, drug administration should be interrupted and ALT, AST, ALP and BILI trends should be followed closely.

Follow, investigate and monitor subject-level data until resolution, record and report all findings.

Handling Liver Test Elevations

Source: www.FDA.gov CDISC 2020 China Interchange | #CDISCChina #ClearDataClearImpact22

Thank You

Questions?

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CDISC 2020 China Interchange

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