ReviewPost screenFDA-approved drug labeling for the study of drug-induced liver injury☆
Introduction
Many drugs have either been discontinued from clinical trials or withdrawn from the market after being approved because of hepatic adverse effects 1, 2. Some of these adverse events can be serious in nature as evidenced by drug-induced liver injury (DILI) being listed as the leading cause of acute liver failure in the USA [3]. Thus, DILI has become one of the most important concerns in the drug development and approval process 4, 5. DILI has also been identified by the FDA Regulatory Science Initiatives as a key area of focus in a concerted effort to broaden the agency's knowledge for the better evaluation of tools and safety biomarkers (http://www.fda.gov/ScienceResearch/SpecialTopics/RegulatoryScience/ucm228131.htm).
Some drugs are more likely to cause hepatotoxicity or liver injury than others, and severe DILI is of most concern. Recently, the FDA has published guidelines for assessing the potential for a drug to cause severe DILI in premarketing clinical evaluation [6]. The toxicological community has made great efforts in developing biomarkers and methodologies to assess hepatotoxicity, including DILI beyond classical animal testing, for all chemicals. The representative methods include, but are not limited to, QSAR assessments [7], in vitro assays [8], high-content screening assays [9] and ‘omics’ studies [10]. Some of these approaches are being evaluated by large government-initiated efforts for developing alternative methodologies for toxicity assessment, such as Tox21 [11] and ToxCast [12] in the USA, and the REACH program [13] in Europe. All of these efforts require a list of drugs with well-annotated DILI potential to guide the methodology development and assess their performance characteristics (i.e. sensitivity and specificity) [14].
A drug classification scheme is essential to facilitate the community-wide effort to evaluate the performance characteristics of existing DILI biomarkers and discover novel DILI biomarkers. However, there is no commonly adopted practice by which the research community can classify a drug's DILI potential in humans. Our study focused on using FDA-approved drug labels to develop a systematic and objective classification scheme for categorizing the DILI potential of a drug. This approach can be used for retrospective analysis of drugs to support studies to identify DILI biomarkers using emerging molecular technologies, thus improving drug safety and development.
Section snippets
Drug labeling
The assessment of hepatotoxic risk associated with individual drugs is a challenge [15]. Three attributes of a drug are important for its DILI assessment: (i) causality – is liver injury caused by a drug or other causes? (ii) incidence – how many cases are deemed significant? and (iii) severity – how severe an injury is considered as a clinically relevant DILI [e.g. elevated alanine transaminase (ALT), Hy's law, disability and hospitalization, liver failure, liver transplantation or death]? The
Using drug labeling to classify the DILI potential of drugs
The overall classification scheme to assess the potential of drugs to cause DILI is presented in Fig. 1 and explained in the following three subsections.
Benchmark dataset
To serve as a benchmark dataset, we compiled a drug list that satisfied the following criteria: (i) has an FDA-approved label; (ii) for human use only; (iii) contains a single active molecule in the dosage form; (iv) administered through oral or parenteral route; (v) approved for over ten years and (vi) commercially available and affordable for future study. These criteria were deliberately chosen based on certain rationales; for example, we only included drugs with a single active ingredient
Caveats of using drug labeling
Many inherent defects are associated with drug labeling. Drafting a drug's label by the drug manufacturer is a complex process involving not only safety concerns but also efficacy, benefit:risk, legal and other considerations. The liver safety profile could therefore be worded differently for drugs with different indications, efficacy and benefit:risk ratios, despite similar hepatic risks. Because the language regarding appropriate wording and the placement of safety-related information is
Concluding remarks
Labeling is not perfect because it is an opinion-based rather than evidence-based process. Moreover, the labeling has been in existence for >40 years, and the terms used in the labels were not devised according to a scientifically justified master plan over the years and its usage has been evolving. Despite imperfections and limitations the labeling still reflects serious thought and consensus by experts and, in practice, is ‘the closest that one can get to the truth regarding the scientific
Acknowledgements
The report study is a part of FDA's Liver Toxicity Knowledge Base (LTKB) project that is supported by the FDA's Critical Path Initiative, the Office of Women's Health and the Chief Scientist Challenge Grant. Vikrant Vijay, Qiang Shi and Zhichao Liu greatly appreciate the opportunity to work at NCTR through the ORISE program. The authors have no conflicts of interest related to this study.
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Disclaimer: The views presented in this article do not necessarily reflect those of the US Food and Drug Administration.
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These authors contributed equally to this paper.