Japanese Journal of Pharmacoepidemiology/Yakuzai ekigaku Vol. 21(2016 - 2017) No. 2

Objective：The objective of this study was to apply Least Absolute Shrinkage and Selection Operator （LASSO）logistic regression to detection of adverse drug reaction （ADR） signals using an electronic health records database as a comprehensive and quantitative method to supplement the current pharmacovigilance activities in Japan.

Design：case-control study

Methods：We analyzed data from 40767 inpatients using a single-institution hospital database and identified two ADRs, suspected pancreatitis and thrombocytopenia, using abnormal laboratory test results. LASSO logistic regression analysis was applied to detect ADR signals with adjustment for age, sex, comorbidities and medical procedures. The positive predictive value （PPV） was calculated using reference standard of known drug-ADR associations based on drug product labels.

Results：The number of case group was 6735 for suspected pancreatitis and 11561 for thrombocytopenia. The number of ADR signals detected using LASSO logistic regression was 27 for suspected pancreatitis and 40 for thrombocytopenia. The calculated PPV was 3.7% for suspected pancreatitis and 55.0% for thrombocytopenia.

Conclusion：LASSO logistic regression analysis efficiently detects ADR signals by adjusting for confounding factors such as comorbidities and medical procedures. The false positive signals may contain unknown signals and further signal assessment will be needed.

To identify the most frequently reported preferred terms （PTs） in the cases of rheumatoid arthritis （RA） patients treated with immunosuppressive biological drugs as suspected drugs, we analyzed the cases in the Japanese Adverse Drug Event Report （JADER） database. We found that pneumonia, interstitial lung disease, Pneumocystis jiroveci pneumonia （PCP), cellulitis, sepsis, and herpes zoster were the most frequently reported PTs. We obtained the reporting odds ratio （ROR） and the time to onset of these six PTs and compared them in the cases reported for each immunosuppressant as a suspected drug. We focused on RA treatment, including five tumor necrosis factor （TNF） antagonists （infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol). For pneumonia, interstitial lung disease and sepsis, no specific correlation was observed for each immunosuppressant for RA. In the case of PCP, the highest ROR was observed in the patients treated with infliximab. The time to onset of PCP in the infliximab-treated patients （median, 0.19 yr） was significantly shorter than the onset time in the patients treated with tocilizumab, an interleukin-6 receptor blocker that is another type of drug for RA（0.32 yr, p<0.01, Mann-Whitney test). The onset time in the patients treated with golimumab （0.24 yr） was also significantly shorter than the onset time for tocilizumab（p<0.05), but the ROR was not as high. These results suggested a correlation between PCP and infliximab. In the cases of cellulitis and herpes zoster, a similar correlation was observed with tocilizumab and certolizumab pegol, respectively. We should consider these results when patients have a respiratory disorder or skin/subcutaneous tissue disorder.

Medicines are fundamental components of treatment, management and control of various diseases. However, despite all their benefits, adverse reactions can be evoked by the use of medicines. Medicinal products achieve maximum advantage when they are appropriately used based on the sound understanding of their risks and benefits. To achieve this, evaluation and monitoring of the safety of medicines under real-life conditions, the appropriate pharmacovigilance systems, are essential. The World Health Organization (WHO) is a specialised agency of the United Nations which commits broad range of works to secure international public health. Pharmacovigilance is embraced as the WHO Programme for International Drug Monitoring (PIDM), which is led and organised by the Safety and Vigilance of Medicines group in the Department of Essential Medicines and Health Products in WHO. Pharmacovigilance is defined by the WHO as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem” . Any other drug-related problems include such as substandard medicine, medication error, lack of efficacy, misuse, abuse, and Substandard/Spurious/Falsely-labelled/Falsified/Counterfeit (SSFFC) products. Whilst the world has made significant progresses in accessing essential medicines through the global efforts such as the UN Millennium Development Goals (MDGs), pharmacovigilance system is not well enough developed. The access to new medicines or the use of medicines in new environments can bring issues to concern. This article outlines the WHO PIDM, the core programme of pharmacovigilance in WHO, on its development, overview and current status. In addition, Safety and Vigilance of Medicines group's activities in order to tackle above concerns are also introduced.