13 Predicting the Risks of Drug-Induced Liver Injury …
263
(i.e., severity, causality, and incidence) mentioned above [1]. We developed a schema
to gather the information from FDA-approved drug labeling to annotate DILI risk
and created a benchmark dataset which contained 287 drugs that were categorized
into three levels of DILI severity: most-DILI-concern, less-DILI-concern, and noDILI-concern [33]. Specifically, the 137 drugs categorized as most-DILI-concern
are those that were suspended, withdrawn, or issued a black box warning due to
hepatotoxicity or had gotten warnings and precautions with moderate or severe DILI
concern. Eighty-five drugs categorized as less-DILI-concern had been issued warnings and precaution with mild DILI concern or only recorded hepatotoxicity in the
Adverse Reactions section of drug labels. Sixty-five drugs listed as no-DILI-concern
are those with no DILI concern mentioned in their drug labels.
The safety data contained in drug labeling are not perfect. A major concern of drug
labels was weakness in causality assessment [1], i.e., the definite causal relationship
is not mandatorily required for drug labeling, and the regulators were authorized
by law to issue a warning when a clinically significant hazard is identified for a
drug with reasonable evidence of causality (http://www.accessdata.fda.gov/scripts/
cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=201.57). Additionally, any modification or
updating of the safety information in drug labeling is a stringent and lengthy process
that likely causes a time lag from the most updated clinical findings [39]. Meanwhile,
case reports could have better timing and be more sensitive to any potential alert
signals caused by drugs. Therefore, by incorporating the case report information
derived from up-to-date literature and on-going DILI research projects such as the
US DILIN project, the drug labeling-based annotation of DILI risk could be further
improved.
Upon these considerations, we further refined the labeling-based annotation
schema by weighing evidence of case reports together with the information from
FDA-approved drug labeling to improve the accuracy of DILI annotation. More
specifically, the refined annotation schema was built upon a collection of well-vetted
cases (verified via thorough case evaluation by DILI experts) and adjudicated cases
(verified using the standardized clinical causality assessment system, i.e., Roussel
Uclaf Causality Assessment Method [40]). With this collected causality information,
the DILI risk of individual drugs was re-evaluated by complementing drug labeling
with available evidence of verified causality. This new schema classified drugs into
four categories as detailed as below:
• Withdrawn drugs and those with a black box warning for severe liver injury were
classified as verified most-DILI-concern (
v Most-DILI-concern) drugs because
they are consistently classified as high DILI risk among several published datasets.
• For those drugs which had been warned with severe or moderate DILI occurrence
in their labels (i.e., isoniazid) [1], the verification process of causality is needed for
the assessment in the new schema: The causality verified drugs will be classified
as the
v Most-DILI-concern, otherwise will be reassigned as “Ambiguous DILIconcern.”
263
(i.e., severity, causality, and incidence) mentioned above [1]. We developed a schema
to gather the information from FDA-approved drug labeling to annotate DILI risk
and created a benchmark dataset which contained 287 drugs that were categorized
into three levels of DILI severity: most-DILI-concern, less-DILI-concern, and noDILI-concern [33]. Specifically, the 137 drugs categorized as most-DILI-concern
are those that were suspended, withdrawn, or issued a black box warning due to
hepatotoxicity or had gotten warnings and precautions with moderate or severe DILI
concern. Eighty-five drugs categorized as less-DILI-concern had been issued warnings and precaution with mild DILI concern or only recorded hepatotoxicity in the
Adverse Reactions section of drug labels. Sixty-five drugs listed as no-DILI-concern
are those with no DILI concern mentioned in their drug labels.
The safety data contained in drug labeling are not perfect. A major concern of drug
labels was weakness in causality assessment [1], i.e., the definite causal relationship
is not mandatorily required for drug labeling, and the regulators were authorized
by law to issue a warning when a clinically significant hazard is identified for a
drug with reasonable evidence of causality (http://www.accessdata.fda.gov/scripts/
cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=201.57). Additionally, any modification or
updating of the safety information in drug labeling is a stringent and lengthy process
that likely causes a time lag from the most updated clinical findings [39]. Meanwhile,
case reports could have better timing and be more sensitive to any potential alert
signals caused by drugs. Therefore, by incorporating the case report information
derived from up-to-date literature and on-going DILI research projects such as the
US DILIN project, the drug labeling-based annotation of DILI risk could be further
improved.
Upon these considerations, we further refined the labeling-based annotation
schema by weighing evidence of case reports together with the information from
FDA-approved drug labeling to improve the accuracy of DILI annotation. More
specifically, the refined annotation schema was built upon a collection of well-vetted
cases (verified via thorough case evaluation by DILI experts) and adjudicated cases
(verified using the standardized clinical causality assessment system, i.e., Roussel
Uclaf Causality Assessment Method [40]). With this collected causality information,
the DILI risk of individual drugs was re-evaluated by complementing drug labeling
with available evidence of verified causality. This new schema classified drugs into
four categories as detailed as below:
• Withdrawn drugs and those with a black box warning for severe liver injury were
classified as verified most-DILI-concern (
v Most-DILI-concern) drugs because
they are consistently classified as high DILI risk among several published datasets.
• For those drugs which had been warned with severe or moderate DILI occurrence
in their labels (i.e., isoniazid) [1], the verification process of causality is needed for
the assessment in the new schema: The causality verified drugs will be classified
as the
v Most-DILI-concern, otherwise will be reassigned as “Ambiguous DILIconcern.”