The effect of clinical pharmacists’ intervention in adverse drug reaction reporting: a retrospective analysis with a 9-year interrupted time series

The concept of drug safety/pharmacovigilance is raising awareness of the various effects of drugs [1]. The establishment of adverse drug reactions (ADRs) databases to collect ADRs reports and evaluate the safety of marketed drugs is important to help healthcare professionals learn more about drugs and ensure their safety. In China, ADRs are primarily reported by healthcare facilities every month via the spontaneous reporting system (SRS) [2]. Although the SRS is an ADRs reporting platform, it cannot spot intentionally or inadvertently missed reports. Moreover, the content and quality of ADRs reports are subject to the reporter's knowledge and background, clinical experience, and patience. In fact, studies show that approximately 10% of inpatients have treatment-related ADRs each year, but less than 5% of these are reported. The actual number of ADRs is much greater than the number of reported ADRs [3]. The China National Centre for Adverse Drug Reaction Monitoring (CNCAM) has three main sources of ADRs reporting, which are medical institutions, drug distributors, and drug manufacturers [4]. In 2020, the CNCAM [2] received a total of 1.676 million ADRs reports, of which 85.4% were spontaneously reported by healthcare facilities [5]. ADRs reporting relies on individual reporters, and no mandatory reporting laws or regulations have been established [6]. In the current healthcare system in China, tens of thousands of ADRs could go unreported each year unless hospitals actively report them [7].

Clinical pharmacists (CPhs) review unusual medication records during treatment and promptly communicate with clinicians to verify ADRs under-reporting, thereby improving the rate, timeliness, and accuracy of ADRs reporting [8]. On June 1, 2015, we implemented an ADR reporting method with CPhs intervention at our hospital, in which a team of CPhs detected ADRs among hospital patients and promptly reminded clinicians to report them. In cases of potential ADRs, CPhs assessed causality, verified the event with clinicians, and reminded the clinicians to report any missed ADRs. In addition, CPhs reviewed ADRs reports for missing items (required items include a personal history of the ADRs, family history of the ADRs, lifestyle factors, medical history, concomitant medications, description of the ADRs [including symptoms, signs, clinical tests], measures taken to treat the ADRs, improvement or resolution of the ADRs after drug discontinuation or dose reduction, ADRs recurrence after the resumption of the suspected drug, and causality) to reduce potential under-reporting and omission and promote the standardization of ADRs reporting. In this paper, we introduce an ADRs reporting method with CPhs intervention that was implemented on June 1, 2015, in a Grade A, Class 3 college teaching hospital in China. Using an interrupted time series (ITS), we retrospectively analysed the number of inpatient ADRs submitted to the CNCAM per month, the number of unreported ADRs per month, and the standardized ADRs reporting rate per month in 2010–2019 to investigate the immediate and long-term effects of CPhs intervention on ADRs reporting.

Using ITS, we retrospectively analyzed the effect of a CPhs ADRs reporting intervention on the number of inpatient ADR reports submitted to the CNCAM per month, the number of unreported ADRs per month, and the standardized ADR reporting rate per month in a Grade A, Class 3 hospital in China. Given that hospital patients are at risk for ADRs and that the team of CPhs developed a DRC that had hospital patients as the target population, we used hospital patients as the study group for data collection and excluded clinic patients and emergency patients, whose ARDs may not be promptly detected and/or reported. With ITS, data are segmented at equal intervals for processing and analysis. Therefore, ITS is one of the best statistical methods for retrospective analyses [23‐25]. We extracted monthly data over a 9-year period and performed an ITS analysis to analyze the effect of the CPhs ADRs reporting intervention on the number of ADRs reports, the number of unreported ADRs, and the standardized ADRs reporting rate; additionally, we determined the long-term trends in these outcomes.

The number of inpatient ADRs reports submitted by our hospital to the CNCAM immediately increased 10.44 fold after the intervention, indicating a marked immediate effect of the intervention and highlighting the number of unreported ADRs. The number of inpatient ADRs reports submitted to the CNCAM per month declined slightly starting at Month 2, However, we consider that there may be multiple factors that induce this result. First, after feedback from physicians, it was considered that it might be related to avoidance of allergy-prone medications. That is, with the intervention of CPhs, clinicians are becoming more aware of reporting ADRs, and with the accumulation of experience in ADR reporting and medication use, physicians also try to avoid prescribing ADR-prone medications for their patients to reduce the risk of ADRs. Of course, this is from a few physician responses and further statistics on drug use are still needed. Second, it may be related to the timing of the intervention. This is because according to the current requirements in China, the time to submit an ADRs report depends on the severity and anticipation of the ADR. Thus some unexpected or serious ADRs must be reported within 15 days, those leading to death must be reported immediately, and others must be reported within 30 days, and this time accommodation may have led to a lag in reporting or nondetection of some ADRs, making the effect of the intervention decrease over time [11]。In addition, it has been suggested in the literature that regular training in the reporting of ADRs during the intervention phase of ongoing training can have a positive impact on the reporting of ADRs [27] Considering that the intervention of CPhs in this study did not add regular training for the medical population, this may be another reason for the decrease in reporting over time. Further analysis showed that the number of unreported ADRs decreased by approximately 40.94 fold during the first month of the CPhs intervention, and this number remained largely unchanged after Month 2, suggesting that the intervention effectively curbed ADR under-reporting. Furthermore, a focus on the quantity rather than the quality of ADRs reports may result in bias in subsequent pharmacovigilance studies based on ADRs reports. The standardized ADRs reporting rate (per month) was increased by 4.32 fold after the intervention. In summary, the CPhs ADRs reporting intervention played an active role in improving the number of ADRs reports and standardization. It should be mentioned, however, that this method was developed by the CPhs as a DRC based on hospital medication practices, which means that the CPhs' method has significantly improved the reporting of ADRs to some extent, but it is still not able to identify 100% of patients who may have ADRs (mainly those who present with ADRs but are not treated with medications), and there is no method or system available today that can identify 100% of ADRs. This is a limitation of the method and an important issue for CPhs to address.

ADRs are still a serious problem worldwide. Some studies show that elderly patients have become an at-risk population for ADRs [28]. ADRs increase the financial burden on patients and the healthcare system [29‐31]. Furthermore, race, region, and lifestyle have major impacts on ADRs throughout the world [32]. ADRs reporting is very important as it enhances drug safety, facilitates post-market evaluation, and is the foundation for global pharmacovigilance studies [33]. However, under-reporting, delayed reporting, and incomplete reports remain common issues in ADRs reporting [34]. China has the largest population in the world, but its ADRs reporting rate is much lower than that of other countries. Comparing data from 15 countries from 2017 to 2018, China was unable to collect ADRs reported directly by consumers due to the lack of a consumer reporting system. The near-zero direct reporting rate by consumers cannot be compared to the 2.6% in Australia, 6.6.% in Belgium, 36% in Estonia, 21% in Finland, 16% in Germany, 9% in Greece, 36% in Ireland, 5% in Latvia Lithuania 12%, Portugal 5%, Slovakia 38.8%, and Spain 6.8% reporting rates [35]. In China, the spontaneous ADRs reporting model relies on healthcare facilities as primary reporters. Moreover, it relies on healthcare professionals’ awareness of ADRs to ensure patient safety and prompt reporting. A meta-analysis has shown that pharmacists can reduce the incidence of posthospital medication errors through guidance [36]. Our hospital is one of the highest-level hospitals in China. Our ADRs reporting situation is representative of that in other large general hospitals in China. In fact, in 2008, we launched a pharmacovigilance program. However, in this program, the CPhs were only responsible for uploading the reports submitted by the clinic and did not proactively establish methods to participate in the identification and quality management of ADRs. Therefore, in the 2008 ADRs report, due to a lack of effective management measures, only 93 ADRs were reported, of these, only 15 reports (16.13%) met the reporting standard, despite 45,169 admissions that year. These data and quality cannot reflect real-world ADRs. We understand that ADR reporting is critical to clinical research, and that the quality of clear, accurate, and detailed reporting is more likely to give a more precise orientation to medical research. In June 2015, a team of CPhs developed a DRC based on the clinical pattern of drug use and the principle of symptomatic care and then reviewed routine drug use in clinical practice. This method successfully improved the number of ADRs reports, underreporting, and standardization of ADRs reporting. In particular, in terms of improving the quality of reporting, the intervention of CPhs has led to a rapid increase in the standard rate of reporting the content of ADRs in a short period of time compared to before the involvement of CPhs and has maintained the subsequent reporting standards at a high level. These improvements have facilitated the monitoring of drug safety. However, it needs to be suggested that, considering that the statistics were performed on visible symptom ADRs in this study, further studies are still needed to observe whether the method is also effective in identifying ADRs without visible symptoms. In addition, this method can be used to establish a DRC that meets the local conditions according to the medication habits of medical institutions in different regions, so it has the characteristics of feasibility and good adaptability.

This retrospective analysis shows that CPhs intervention in ADRs reporting significantly improves the number of ADRs reports, reduces nonreporting, and improves the standardization of ADRs reports, indicating that CPhs play an active role in ADRs reporting. However, this method has some limitations. As a method to improve ADR identification, it enables effective identification of ADRs that are present and underreported to alert CPhs for timely reporting of ADRs, but not for patients with unmedicated ADRs. ADRs are still considered unpredictable worldwide, and ADRs-predicting systems and software are lacking [37]. Researchers are working on systems for effective ADRs detection and reporting, but they have yet to identify methods for predicting ADRs. We realized during data collection in this study that early adverse reactions without obvious symptoms are difficult to detect. For this reason, on the basis of ADRs reported over the 9 years, we plan to investigate how to predict ADRs based on unusual fluctuations in clinical indicators such as platelets, hemoglobin, albumin, liver function, and kidney function. The goal is to identify potential ADRs to provide early warnings. We will report the results in due time.