Study of serious adverse drug reactions using FDA-approved drug labeling and MedDRA

Leihong Wu; Taylor Ingle; Zhichao Liu; Anna Zhao-Wong; Stephen Harris; Shraddha Thakkar; Guangxu Zhou; Junshuang Yang; Joshua Xu; Darshan Mehta; Weigong Ge; Weida Tong; Hong Fang

doi:10.1186/s12859-019-2628-5

Study of serious adverse drug reactions using FDA-approved drug labeling and MedDRA

BMC Bioinformatics. 2019 Mar 14;20(Suppl 2):97. doi: 10.1186/s12859-019-2628-5.

Authors

Affiliations

¹ National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA.
² MedDRA Maintenance and Support Services Organization, 7575 Colshire Dr., McLean, VA, 22102, USA.
³ National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA. Weida.Tong@fda.hhs.gov.
⁴ National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA. Hong.Fang@fda.hhs.gov.

Abstract

Background: Adverse Drug Reactions (ADRs) are of great public health concern. FDA-approved drug labeling summarizes ADRs of a drug product mainly in three sections, i.e., Boxed Warning (BW), Warnings and Precautions (WP), and Adverse Reactions (AR), where the severity of ADRs are intended to decrease in the order of BW > WP > AR. Several reported studies have extracted ADRs from labeling documents, but most, if not all, did not discriminate the severity of the ADRs by the different labeling sections. Such a practice could overstate or underestimate the impact of certain ADRs to the public health. In this study, we applied the Medical Dictionary for Regulatory Activities (MedDRA) to drug labeling and systematically analyzed and compared the ADRs from the three labeling sections with a specific emphasis on analyzing serious ADRs presented in BW, which is of most drug safety concern.

Results: This study investigated New Drug Application (NDA) labeling documents for 1164 single-ingredient drugs using Oracle Text search to extract MedDRA terms. We found that only a small portion of MedDRA Preferred Terms (PTs), 3819 out of 21,920 or 17.42%, were observed in a whole set of documents. In detail, 466/3819 (12.0%) PTs were in BW, 2023/3819 (53.0%) were in WP, and 2961/3819 (77.5%) were in AR sections. We also found a higher overlap of top 20 occurring BW PTs with WP sections compared to AR sections. Within the MedDRA System Organ Class levels, serious ADRs (sADRs) from BW were prevalent in Nervous System disorders and Vascular disorders. A Hierarchical Cluster Analysis (HCA) revealed that drugs within the same therapeutic category shared the same ADR patterns in BW (e.g., nervous system drug class is highly associated with drug abuse terms such as dependence, substance abuse, and respiratory depression).

Conclusions: This study demonstrated that combining MedDRA standard terminologies with data mining techniques facilitated computer-aided ADR analysis of drug labeling. We also highlighted the importance of labeling sections that differ in seriousness and application in drug safety. Using sADRs primarily related to BW sections, we illustrated a prototype approach for computer-aided ADR monitoring and studies which can be applied to other public health documents.

Keywords: Adverse drug reactions; Boxed Warning; Data mining; Drug labeling; Drug safety; MedDRA; Standard terminology; Structured product labeling.

MeSH terms

Adverse Drug Reaction Reporting Systems / standards*
Data Mining / methods*
Drug Labeling / instrumentation*
Drug-Related Side Effects and Adverse Reactions / diagnosis*
Drug-Related Side Effects and Adverse Reactions / pathology
Humans