Spontaneous Reporting on Adverse Events by Consumers in the United States: An Analysis of the Food and Drug Administration Adverse Event Reporting System Database

Spontaneous Reporting on Adverse Events by Consumers in the United States: An Analysis of the... Drugs - Real World Outcomes (2018) 5:117–128 https://doi.org/10.1007/s40801-018-0134-0 ORIGINAL RESEARCH ARTICLE Spontaneous Reporting on Adverse Events by Consumers in the United States: An Analysis of the Food and Drug Administration Adverse Event Reporting System Database 1 1 Tadashi Toki Shunsuke Ono Published online: 3 May 2018 The Author(s) 2018 Abstract Conclusions Our analysis of voluntary AE reports in the Background Voluntary reports on adverse events (AEs) US FAERS database has shown that voluntary reports submitted by consumers have been facilitated through the tended to include AEs related to subjective symptoms, as in MedWatch program in the United States (US), but few some previous studies on patient reporting in the EU. studies have described the characteristics of voluntary Voluntary reports by consumers seemed to be different reports. from ones by healthcare professionals in important aspects Objective The aim of this study was to reveal the charac- including demographics and reporting behaviors. These teristics of current voluntary reports on AEs reported by findings suggest that the heterogeneities should be consumers and healthcare professionals. addressed appropriately in using spontaneous reports. Methods We performed analysis on voluntary reports of AEs in the US Food and Drug Administration AE Reporting System (FAERS) database submitted in 2016. Key Points We compared reports by consumers with those by health- care professionals. The number of voluntary adverse event (AE) reports Results The number of voluntary reports by consumers has by consumers, which reflect concerns and increased since 2013 in the US. Reports by consumers were restrictions specific to consumers, has apparently different from ones by health professionals in several increased since the introduction of the ‘consumer- important aspects such as demographics and outcomes of friendly’ reporting form FDA3500B in 2013, patients, AEs, and suspect drugs. The proportion of reports accounting for about half of the total AE reports in on female patients and on disability as a patient outcome the second quarter of 2016. were higher in reports by consumers than in those by healthcare professionals. Consumers more frequently Reports by consumers were different from ones by health professionals in important aspects such as reported concomitant drugs compared with healthcare demographics and outcomes of patients, AEs, and professionals. Time to report varied among the occupations suspect drugs. Report completeness and time-to- and depending on seriousness of outcomes. report also varied depending on the occupation of reporters. Electronic supplementary material The online version of this Observed characteristics in spontaneous reporting in article (https://doi.org/10.1007/s40801-018-0134-0) contains supple- mentary material, which is available to authorized users. the US should be considered in using AE reports in pharmacovigilance activities, especially when AE & Shunsuke Ono reports are compared with ones in different shun-ono@mol.f.u-tokyo.ac.jp countries/regions. Laboratory of Pharmaceutical Regulation and Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan 118 T. Toki, S. Ono types and variations of data sources, because the internal 1 Introduction and external validity of analyses using the databases totally Recent changes in pharmaceutical markets and regulations, depend on them. Regarding that perspective, however, spontaneous reports have attracted less attention than including introduction of new accelerated approval path- ways [1–3], new lines of therapies with innovative phar- obligatory reports from the industry. There are a couple of studies on spontaneous reports by nurses and physicians in macological mechanisms from molecular-targeted drugs to immune checkpoint inhibitors and to cell therapies, and locally established databases of AE reports, but there have been few analytical studies focusing on spontaneous growing expectations from patients for new therapies under development, have prompted regulators and industries to reporting by consumers in the US [22–25]. In the European Union (EU), patient-oriented reporting has grown gradu- introduce new drugs faster and more efficiently [4]. These ally since the 2000s, and current situations have been trends have made postmarketing pharmacovigilance more described in previous studies [25–30]. In one study it was important than ever [5]. The United States (US) Food and concluded that patient reporting successfully comple- Drug Administration (FDA) Adverse Event (AE) Report- ing System (FAERS) database, one of the largest phar- mented reporting by healthcare professionals, and the conclusion was consistent with that of a study in the UK macovigilance databases, plays a key role in both collecting and providing data on drug-related AEs. In the [31, 32]. Another study using the database of the Dutch Pharmacovigilance Center Lareb showed that patients US, the FAERS database gives the FDA critical signals and a decision basis to take regulatory actions such as ordering report clinical information at a similar level to healthcare professionals. labeling changes in the warning and/or precaution sections In this study, we aimed to identify the characteristics of to improve drug use in markets [6, 7]. Epidemiologists recent voluntary reports submitted by consumers and worldwide use the database to detect novel drug-related compare them with those by healthcare professionals. We safety events, to identify possible mechanisms of AEs, and discussed what backgrounds have led to the observed dif- to explore efficient methods to detect potential drug-related ferences, especially focusing on how information available AEs [8–14]. The database has been used beyond the realm of safety. For example, several researchers have recently on AEs could influence reporters’ attitudes to AE reporting. studied drug–drug interactions with new approaches using the FAERS database, which could lead to discovery of 2 Methods promising new concomitant uses of drugs in certain ther- apeutic areas [15, 16]. We analyzed the FAERS database and examined the For all purposes, the integrity of databases is a critical condition for users to obtain unbiased conclusions. Under- reports submitted by consumers and healthcare profes- sionals. We showed the transition of the numbers of vol- reporting has been a serious issue that afflicts pharma- untary reports in the US (Fig. 1), and conducted several covigilance activities worldwide [6, 17]. Previous studies showed that under-reporting was caused by many factors, descriptive analyses to reveal the characteristics of current voluntary reports. All the descriptive analyses were based including inevitable dependency on reporters volunteering incentives and lack of awareness of how to use public on the reports (25,814 reports) in the first and second quarter of 2016, and the analyses related to primary suspect reporting systems, or even their existence [18, 19]. A practical approach to improve the situation of under-re- drugs were based on reports for which primary suspect drugs were registered in the SIDER4.1 database. porting is to publicize the reporting system and to encourage not only healthcare professionals but also the 2.1 Food and Drug Administration (FDA) Adverse consumers who actually experience AEs, and their fami- Event (AE) Reporting System (FAERS) Data lies, to submit AE reports to the FDA. The FDA has also Preparation made efforts to reduce undesirable disproportionality (e.g., over- or under-representation of specific populations) in the FAERS. To alleviate these concerns, the FDA has contin- We used the JAPIC AERS database, comprising the FAERS database cleaned by the Japan Pharmaceutical uously expanded the MedWatch program for more than 20 years. The FDA introduced the first voluntary reporting Information Center (JAPIC), which was provided for our study under a collaborative research contract. During data form FDA3500 in 1993 and the form FDA3500B in 2013, a voluntary consumer-friendly reporting form, to encourage cleaning, JAPIC eliminated redundant cases, adjusted units to make them uniform, mapped drug names onto their drug reporting by patients [20, 21]. It is important for database users to acknowledge basic name dictionary, and refreshed preferred terms (PTs) in the Medical Dictionary for Regulatory Activities (MedDRA, characteristics of spontaneous safety databases, including ver.19.1) terminology. Spontaneous Reporting on Adverse Events in the US 119 Fig. 1 Changes in the number of voluntary reports by consumers and which suggests that most UNs after Q3 of 2013 are consumers using healthcare professionals. The bar graph shows the number of the FDA3500B form. AE adverse event, CN consumer, MD physician, quarterly reports. The ‘only-for-consumer’ FDA3500B form was OT other healthcare professional, PH pharmacist, UN unknown introduced in 2013, and AE reports by unknown occupation reporters occupation reporter (UN) have increased sharply since the 3rd quarter (Q3) of 2013, 2.2 Definition of Reporters reports by ‘unknown occupation’ reporters. We used the following abbreviations for each type of reporter: CNs for We classified reporters into consumers, pharmacists, consumers, UNs for unknown occupation reporters (in- physicians, and other healthcare professionals according to cluding consumers using FDA3500B), PHs for pharma- the reporter’s occupation on the form. The main focus of cists, MDs for physicians, and OTs for other healthcare this research was to reveal the characteristics of voluntary professionals. reports (e.g., demographics, background diseases, type of AEs, time-to-report) by consumers in the US and compare 2.3 Additional Data Collection them with reports by healthcare professionals. For this aim, we looked at both the voluntary reports by those who To determine whether AEs in a report were already known clearly identified themselves as ‘consumers’ in the classical (i.e., written in the labels at the time of AE reporting), we voluntary reporting form FDA3500 (Group 1) and the used the SIDER database on marketed chemical medicines voluntary reports in form FDA3500B that lacked the and related adverse drug reactions from drug labels [33]. occupation item because it is intended for use by con- SIDER used the MedDRA dictionary to extract side effects sumers (Group 2). The form FDA3500B, which was from labels. The results of this mapping are available under released in 2013 to facilitate consumers’ voluntary reports, a Creative Commons Attribution-Noncommercial-Share has the same items as FDA3500 except for occupation. The Alike 4.0 License. We downloaded the data from the instructions in FDA3500B are easier for consumers to SIDER website on April 18, 2017. Because SIDER version understand, even for first-time users. 4.1 was released on October 21, 2015, we treated the Although the reports in both groups (1 and 2) were adverse drug reactions (ADRs) included in SIDER 4.1 as supposed to be submitted by consumers, another research known ADRs. If one of the AEs in a report was a known question would be on whether the users of the form ADR for the primary suspect drug in the report, we con- FDA3500 might be different from the users of the form sidered that the report had known ADR(s). We collected FDA3500B in some demographic traits as well as AEs and data on safety labeling changes from monthly safety drugs reported. However, the current dataset publicly labeling changes on the FDA’s MedWatch websites [34]. available from FAERS does not have a code showing in Using the archival data we also obtained data on how many which form the report was submitted and it was impossible times the primary suspect drug experienced safety labeling to compare Groups 1 and 2 directly. We therefore tagged changes in the black box warning, warning, and/or pre- Group 1 as the reports by ‘consumers’ and all the reports caution sections. that lacked reporter’s occupation, including Group 2, as 120 T. Toki, S. Ono 2.4 Data Analysis studied decades. Significant proportions of reports in Q1 and Q2 of 2016 were made by PHs (44%) and UNs (37%). The completeness of reports is a quality indicator that Given the fact that 72% of voluntary reports in 2005 were reflects the characteristics of reporters and environments, made by healthcare professionals, including PHs and MDs, including reporters’ motivation for AE reporting. We the contribution of consumers has been steadily on the rise. assessed the completeness in reports by different types of reporters for the following items: patient sex, patient age, 3.2 Contents of Reports: Demographics, patient weight, indications, event date, route of primary Indications, Suspect Drugs, AEs, and Outcomes suspect drug administration, secondary suspect drug(s), and concomitant drugs. We examined the time to report (i.e., The sex ratio of patients was different between the repor- the time between AE occurrence and submission of the AE ters (Fig. 2a). Reports by consumers tended to have AEs report to the FDA) because it is an interesting indicator observed in female patients, while reports from healthcare reflecting reporters’ responsiveness to AE reporting. This professionals did not show such an imbalance. The average indicator reflects various reporting conditions, including patient age was 55.4, 50.5, 56.9, 52.0, and 52.0 years for carefulness, to determine the cause of AEs and priority of reports by CNs, UNs, PHs, MDs, and OTs, respectively AE reporting, which might be especially notable for (Fig. 2b). Patient outcomes were different according to the healthcare professionals. We analyzed the time to report occupation of reporters (Fig. 2c). The proportion of dis- from two aspects. First, we examined possible associations ability cases was much higher in reports by CNs and UNs between the time to report and whether the AEs were than those by healthcare professionals. As expected, reports known at the time of AE occurrence in all cases, ones with by MDs were likely to include hospitalization much more serious outcome, or ones with non-serious outcome. This frequently than those by the other occupations. would offer clues to how responsiveness differs between Typical profiles of AE reports by each occupation were the reporters facing different levels of uncertainties. Sec- described in terms of AEs, primary suspect drug, and ond, we examined time to report by stratifying by whether indication. The types of AEs frequently included were not the primary suspect drug had experienced safety labeling much different among the reports from different occupa- changes, which may raise public awareness of drugs and tions (Table 1). Fatigue, headache, and nausea were AEs and affect healthcare professionals and consumers in reported frequently in the reports from PHs and OTs. different ways. Regarding primary suspect drugs, sofosbuvir was most We used PostgreSQL version 9.3 and Python version 2.7 frequently observed in the reports by CNs, PHs, and OTs for data extraction. Chi square test and Wilcoxon rank-sum (Table 2). test were used for inter-group comparisons. The signifi- Reported indications reflected the indications of primary cance threshold was set at p = 0.05 in all statistical suspect drugs, although indication was missing in most of analyses. the reports (Table 3). In reports with the data available, hepatitis and rheumatoid arthritis were the top two indi- cations reported by CNs, PHs, and OTs. Interestingly, 3 Results indications in the reports by CNs were different from those by the UNs, although it was supposed that both CNs and 3.1 Trend in Spontaneous AE Reporting UNs indicate consumers, as discussed above. The users of FDA3500 and the users of FDA3500B might therefore be From Q4 of 1997 through Q2 of 2016, 482,938 voluntary different in background. reports were submitted to the FDA, 69,267 by consumers, 175,675 by unknown occupation reporters, 138,454 by 3.3 Report Completeness and Time to Report pharmacists, 40,668 by physicians, and 58,874 by other healthcare professionals. The total number of voluntary Completeness of reports differed among the occupations reports increased from 2251 in Q4 of 1997 to 13,866 in Q2 [Online Resource 1, see electronic supplementary material of 2016, with the upward trend especially noticeable since (ESM)]. Patient sex and age were reported in most of the Q3 of 2013 when the consumer-friendly form FDA3500B reports. For the other items, the reporting rate varied by the became an option for consumer reporting (Fig. 1). Because type of reporters. Among them, concomitant drug(s) were the number of reports from consumers using the form reported more often in the reports by CNs and UNs than in FDA3500 diminished after 2013 (CN in Fig. 1), the those by PHs, MDs, and OTs. observed trend indicates that UN reporters after 2013 Reports by OTs had the shortest time to report with a mostly consisted of consumers who used FDA3500B. The median time of 5 days (Fig. 3), while reports by CNs contributions of various reporters have changed in the showed the longest time to report with a median time of Spontaneous Reporting on Adverse Events in the US 121 Fig. 2 Distribution of reports grouped based on patient sex (a), age every 10 years (b), and patient outcome (c). The definition for seriousness of patient outcome in this paper followed the description in the International Conference on Harmonization (ICH) E2 guideline. CA congenital anomaly, CN consumer, DE death, DS disability, HO hospitalization—initial or prolonged, LT life-threatening, MD physician, NS non-serious, OS other serious (important medical event), OT other healthcare professional, PH pharmacist, RI required intervention to prevent permanent impairment/damage, UN unknown occupation reporter. *p \ 0.05 (Chi square test for the ratio of reports with a female patient to those with a male patient vs CN); p \ 0.05 (vs UN) 22 days. The time to report by CNs seemed longer than However, the time to report in consumers’ reports was not that by UNs, suggesting that consumers may use the two affected by seriousness of outcomes. CNs submitted AEs reporting forms differently, or that the users of each form where the primary suspect drug had experienced safety are somewhat different. The median time for PHs, MDs, labeling changes in the black box warning sections earlier and UNs was 9.5, 15, and 15 days, respectively. Time to than other AEs (Online Resource 3, see ESM). In contrast, report was longer in serious cases than in non-serious cases PHs and OTs submitted the AEs earlier when the primary except for the reports by MDs. suspect drug had labeling changes in the warning or pre- We also examined how time to report varied among the caution sections, but not in the black box warning. occupations depending on whether the AE was known or not, and on whether the primary suspect drug had experienced safety labeling changes (Fig. 4, Online Resource 2 and 3, see 4 Discussion ESM). In all the reports by PHs, the time to report for known AEs was shorter by 1 day (median) than that for unknown Our analysis showed that consumers’ reports, which have AEs. In the reports with serious outcome, PHs reported accounted for a significant portion of recent increases in the known ADRs slowly, and OTs reported them rather fast. number of voluntary reports, seem to have information that 122 T. Toki, S. Ono Table 1 Top 10 MedDRA preferred terms (PTs) for AEs ranked by the most frequently reported by each type of reporter CN No. of UN No. of PH No. of MD No. of OT No. of reports reports reports reports reports 1 Headache 43 Headache 404 Fatigue 808 Nausea 54 Fatigue 195 2 Nausea 42 Fatigue 376 Headache 622 Product 54 Headache 159 substitution issue 3 Dizziness 37 Dizziness 347 Nausea 417 Pyrexia 48 Nausea 126 4 Dyspnea 37 Nausea 345 Diarrhea 304 Drug ineffective 43 Diarrhea 77 5 Fatigue 37 Drug 316 Rash 221 Diarrhea 41 Rash 63 ineffective 6 Diarrhea 34 Pain 313 Dizziness 189 Fatigue 38 Product 62 substitution issue 7 Pain 27 Arthralgia 312 Insomnia 181 Dizziness 33 Dizziness 54 8 Asthenia 23 Blood glucose 296 Dyspnea 178 Seizure 33 Insomnia 47 increased 9 Vomiting 22 Pain in 288 Vomiting 178 Vomiting 33 Vomiting 46 extremity 10 Chest 19 Insomnia 257 Pruritus 138 Headache 32 Drug ineffective 38 pain AE adverse event, CN consumer, MD physician, OT other healthcare professional, PH pharmacist, UN unknown occupation reporter Table 2 Top 10 primary suspect drugs ranked by the most frequently reported by each type of reporter CN No. of UN No. of PH No. of MD No. of OT No. of reports reports reports reports reports 1 Sofosbuvir 71 Metformin 704 Sofosbuvir 1250 Cisplatin 55 Sofosbuvir 345 2 Ritonavir 26 Levonorgestrel 314 Everolimus 366 Temozolomide 41 Ribavirin 78 3 Metformin 22 Levofloxacin 287 Warfarin 245 Cyclophosphamide 39 Capecitabine 64 4 Capecitabine 16 Ciprofloxacin 201 Capecitabine 188 Carboplatin 31 Everolimus 52 5 Everolimus 12 Canagliflozin 129 Ribavirin 180 Lamotrigine 28 Emtricitabine 45 6 Ribavirin 12 Etonogestrel 101 Ustekinumab 148 Canagliflozin 17 Tenofovir 45 disoproxil fumarate 7 Apixaban 11 Sofosbuvir 93 Rivaroxaban 125 Bicalutamide 15 Methotrexate 29 8 Deferasirox 11 Sodium 90 Dasatinib 106 Cytarabine 15 Tacrolimus 28 chloride 9 Ciprofloxacin 10 Rivaroxaban 80 Deferasirox 104 Dexamethasone 14 Ivacaftor 27 10 Hydrochlorothiazide 10 Lamotrigine 76 Tobramycin 104 Sofosbuvir 14 Temozolomide 25 CN consumer, MD physician, OT other healthcare professional, PH pharmacist, UN unknown occupation reporter is not necessarily provided by healthcare professionals. system through the MedWatch program in 2013 [20, 21]. Differences were observed not only in AEs, suspect drugs, These efforts apparently have achieved an excellent out- and health outcomes, but also in reporting quality and come in enhancing voluntary reporting. Figure 1 indicates behaviors such as report completeness and time to report. that the total number of voluntary reports in the US has In the US, the FDA has facilitated voluntary reports by increased, especially since 2013, and that consumers seem consumers through several activities such as the release of to have contributed to that increase. This was probably due a new consumer-friendly reporting form FDA3500B and to encouragement and increased public recognition that the refurbishment of the interface of its online reporting patients, as well as healthcare professionals, could report Spontaneous Reporting on Adverse Events in the US 123 Table 3 Top 10 indications ranked by the most frequently reported by each type of reporter CN No. of UN No. of PH No. of MD No. of OT No. of reports reports reports reports reports 1 Hepatitis C 131 Missing 2332 Missing 1312 Missing 342 Missing 479 2 Missing 124 Urinary tract 153 Hepatitis C 688 Type 2 diabetes 21 Hepatitis C 246 infection mellitus 3 Atrial 14 Sinusitis 151 Chronic 372 Hepatitis C 18 Chronic hepatitis 90 fibrillation hepatitis C C 4 Hypertension 10 Contraception 132 Atrial 368 Diabetes mellitus 13 Product used for 68 fibrillation unknown indication 5 Breast cancer 9 Hypertension 103 Product used for 345 Chronic hepatitis 12 HIV infection 55 unknown C indication 6 HIV infection 8 Pneumonia 87 Neoplasm 175 Contraception 9 Cystic fibrosis 50 malignant 7 Product used for 8 Depression 84 Cystic fibrosis 149 Rhinitis allergic 9 Rheumatoid 25 unknown arthritis indication 8 Anxiety 7 Bronchitis 72 Hypertension 146 Atrial fibrillation 8 Hypertension 22 9 Pain 7 Pain 69 Pain 145 Attention deficit/ 8 Chronic myeloid 20 hyperactivity leukemia disorder 10 Rheumatoid 7 Hepatitis C 65 HIV infection 122 Epilepsy 8 Attention deficit/ 18 arthritis hyperactivity disorder CN consumer, MD physician, OT other healthcare professional, PH pharmacist, UN unknown occupation reporter Fig. 3 Distribution of time to report stratified by each reporter (a) and the seriousness of patient outcome (b). Boxplot with whiskers with maximum 1.5 interquartile range. Any data not included between whiskers are plotted as an outlier with a dot. If the value for the first quartile is zero, the box is not shown. CN consumer, MD physician, OT other healthcare professional, PH pharmacist, UN unknown occupation reporter. *p \ 0.05 (Wilcoxon rank-sum test) AEs directly to the FDA, especially using the online periods is a problem. For data mining purposes, changes in reporting form. the quality of information must be considered in statisti- The increase in the number of reports is beneficial to cally rigorous ways [17, 35]. Besides the statistical aspects, overall pharmacovigilance activities, but it inevitably safety authorities and drug companies need to decide draws experts’ attention to increasing heterogeneity in the whether and how we should prioritize concerns for specific safety database due to diversified reporting sources. safety issues presented by diverse reporters in current Needless to say, statistical inconsistency between different public health needs. All these issues make it necessary to 124 T. Toki, S. Ono Fig. 4 Distribution of time to report grouped by whether a report included ‘known’ drug- related AEs for all reports (a), reports with serious outcome (b), or reports with non-serious outcome (c). Boxplot with whiskers with maximum 1.5 interquartile range. Any data not included between whiskers are plotted as an outlier with a dot. If the value for the first quartile is zero, the box is not shown. AE adverse event, CN consumer, MD physician, OT other healthcare professional, PH pharmacist, UN unknown occupation reporter *p \ 0.05 (Wilcoxon rank-sum test) clarify how consumers are different from traditional in patients. In contrast, healthcare professionals rarely reporters, mostly healthcare professionals, and also to test reported disability cases. This indicates that reports by whether reports from consumers who choose the new consumers can add information about AEs that may not be reporting form and routes are different from reports by emphasized by healthcare professionals, and this is con- consumers who choose (or chose) the traditional reporting sistent with a recent systematic review of the literature on form. patient reporting [38]. Our analysis identified several interesting features in US Report completeness has been considered an indicator voluntary reports. We found some disparities in patient sex for well documented AE reports and used for data mining reported by different occupations. Previous studies showed in the World Health Organization’s pharmacovigilance that female patients had a 1.5- to 1.7-fold greater risk of database VigiBase [35, 39]. A recent paper showed that developing an ADR, which might be caused by sex dif- voluntary reports have a higher level of report complete- ferences in pharmacological response [36, 37]. Another ness than do reports from drug companies: the complete- recent study presented the same sex disparity and also ness of all four items (sex, age, event date, and medical showed that healthcare professionals tended to report terms) was 86.2% in serious reports submitted directly to ADRs of male patients more than other types of reporters the FDA (i.e., voluntary reports), as compared with 40.4% did [28]. Our results indicate that consumers were more in manufacturer-expedited reports and 51.3% in manufac- likely to report AEs of female patients than were healthcare turer periodic reports, in 2014 [40]. We examined three professionals (Fig. 2), which was concordant with the items (i.e., event date, indication, and route of primary findings of previous studies. suspect drug) for which data are frequently missing in the Regarding reported patient outcomes, we found that FAERS database, and other important items including sex, consumers were likely to report AEs that caused disability age, and weight. The report completeness rates for these Spontaneous Reporting on Adverse Events in the US 125 items were almost the same in reports from different median time to report AEs by any reporter in the US was reporters, but some findings suggest possible differences in shorter than that in the EU. These differences in time to reporters’ interest and environment. For example, con- report are likely to reflect differences in reporting path- sumers’ reports lack the event date more often than do the ways: the voluntary AE reports in this research were other reports (Online Resource 1, see ESM). This may be directly submitted to the FDA, while some reports in the unsurprising, however, because AEs are detected, recorded, EU arrived at the authority via companies or other regu- and reported retrospectively based on the records and/or latory agencies. Different reporting times may also be memories available to the reporters. The fact that con- influenced by different cultures and histories surrounding sumers showed the longest time to report with a median the reporting systems and use of drugs, such as publicity time of 22 days (Fig. 3) may support the finding. around medicinal products, as a previous report suggested The number of concomitant drugs may reflect reporters’ [43]. With respect to suspect drugs, Table 2 indicates that availability of information, and how meticulous the MDs report AEs of oncologic injection drugs (e.g., cis- reporters are within real-world constraints. We found that platin and carboplatin) but consumers do not, which sug- consumers reported more concomitant drugs than did other gests that MDs and consumers report different AEs in reporters (Online Resource 1, see ESM). Our preliminary different settings, and may explain our observation (at least analysis showed that the number of concomitant drugs did partly) that time to report was much shorter in MDs than in not correlate with report completeness for any other items, consumers. It is worthwhile investigating whether this suggesting that this would not be a quality measure for reflects differences in the publicity and maturation of the general purposes. AE reporting system between the two regions. In general, consumers are thought to have less access to It was also shown that time to report by consumers was information on drug-related AEs in drug labels than do longer than that by pharmacists and other healthcare pro- healthcare professionals. Consumers do not have expertise fessionals, and almost equal to that by physicians (Fig. 3a). in pharmacovigilance activities, either. We had expected Comparisons between serious and non-serious cases that previous knowledge about AEs would affect reporting showed that time to report was longer in serious cases than behaviors differently for consumers and healthcare pro- in non-serious cases except in the reports by physicians fessionals, but our analysis using all the reports did not (Fig. 3b). With regard to whether the AE(s) were already show a clear difference between the two groups (Fig. 4a). written in the labels, interesting differences were observed This is basically in line with a conclusion in a previous between healthcare professionals in reports with serious report that patients can make causality assessment based on outcome(s) (Fig. 4b). Safety labeling changes of primary the available information [31, 32]. We further examined suspect drugs were associated with the time to report of healthcare professionals but not with those of consumers serious ADR cases and found that known ADRs were reported more slowly than unknown ADRs by PHs, and (Online Resource 3, see ESM). Time to report was asso- vice versa by OTs (Fig. 4b). This suggests differences ciated with which section of labeling (i.e., black box seem to exist among healthcare professionals. warning, warning, or precaution) had been revised, but in Histories of labeling revisions were associated with somewhat complicated ways. Interestingly, pharmacists observed differences between consumers and healthcare and other healthcare professionals tended to report earlier professionals in what and how they are likely to report the primary suspect drug for which safety labeling changes (Online Resource 2 and 3, see ESM). A possible expla- occurred in the warning or precaution sections, but not in nation is that healthcare professionals, and MDs in par- the black box warning. ticular, are less likely to be influenced by prior information Causalities behind these findings on time to report are about risk and/or more likely to adhere to their own complex and beyond our scope, but they probably reflect judgement than are consumers. However, it is difficult to diversities in the environment where reporters come to discuss the role of prior information and environment experience and/or be aware of AEs and decide to report based solely on our findings, because there are many AEs to the authority. Some consumers may have difficul- confounding factors. The issuance of regulatory alerts, for ties in reporting their own AE immediately after their example, is a possible confounder that has been investi- recovery, and need to take time to learn how to report AEs gated intensively in many studies [41, 42]. even when they intend to do so. Physicians, who com- Time to report is an interesting measure of promptness monly struggle with time conflicts on a daily basis, may in reporting and may help to describe reporting behaviors. face tradeoffs between voluntary and mandatory reporting. A recent study in the EU showed that median time to report Causal determination for AEs did not seem to play a crit- an ADR was approximately 30 days in spontaneous ical role as shown in Fig. 4 and Online Resource 3 (see reports, regardless of whether it was reported by patients or ESM). This is in line with a previous report that some healthcare professionals [28]. As shown in Fig. 3a, the consumers may be able to identify suspected ADRs 126 T. Toki, S. Ono adequately [31, 32]. To improve efficiency and respon- reporters’ occupations made it difficult to extract data from siveness in the current reporting system, we need to con- ‘real’ consumers. There are no official rules and/or prin- sider real-world mechanisms of reporting behaviors. For ciples on how to handle consumers’ reports in publication example, we need to examine the possible influence of and data mining, and our analysis had to be done under communications such as ‘Dear Healthcare Provider’ letters, such uncertainties. Our analysis did not cover mandatory which are expected to have substantial impacts on report- reports, which limits the generalizability of our results. A ing behaviors [41, 42]. significant portion of AE reporting is done as mandatory Our analysis provided several clues to the heterogeneity reporting, and drug companies play a key role in it. in reports from consumers, which were conveyed in one of Healthcare professionals choose reporting route(s) consid- the two different forms: the traditional form FDA3500 ering types and seriousness of AEs, applicable rules, and (tagged as ‘CN’ in this paper) and the new form many other factors including opportunity costs of report- FDA3500B (tagged as ‘UN’). It is apparently the latter ing. These considerations affect how healthcare profes- form that has contributed to the recent increase in the sionals report AEs voluntarily. Further studies are needed number of AE reports. Although the traditional form users to shed light on such broader aspects and examine the and the new form users were similar in some aspects (e.g., system as a whole. concomitant drugs, report completeness), they were apparently different in other important aspects including reported outcomes and indications, and time to report. It is 5 Conclusion quite natural that consumers use forms differently when a new reporting form and/or route is added to traditional Our analysis of voluntary AE reports in the US FAERS forms/routes, and this might be exactly what regulators database has shown the characteristics of spontaneous intended to facilitate. Our results suggest that database reporting in the US. Voluntary reports tended to include users have to be careful about such heterogeneities when AEs related to subjective symptoms, as in some previous combining or pooling reports made using the different studies on patient reporting in the EU. Voluntary reports by forms, even though they were all submitted by consumers seemed to be different from reports by health- ‘consumers.’ care professionals in demographics and outcomes of Finally, we can discuss our findings with reference to patients, and suspect drugs. They were also different in previous studies in the EU. As discussed above, the aver- report completeness and time to report, which may reflect age time to report in the US was much shorter than that in concerns and environments that are specific to each type of the EU, which may reflect the extent of differences in reporter. Consumers’ choice of voluntary reporting forms regulations and reporting pathway(s) [28]. Reporting may be worth studying further. These findings suggest that behaviors in consumers, including promptness to report, the heterogeneities should be addressed appropriately when may be affected by marketing environments such as direct- using spontaneous reports, especially in the context of to-consumer advertising [43]. Irrespective of these differ- international comparison. ences between the US and European countries, we found Acknowledgements We would like to thank Japan Pharmaceutical that consumers’ reports in both regions are similar in some Information Center (JAPIC) for permitting our use of the JAPIC important aspects. For example, consumers in both regions AERS database under a collaborative research contract. We would tend to report subjective symptoms such as headache, like to thank Editage (http://www.editage.jp) for English language fatigue, and nausea [28]. Avery et al. investigated patient editing. reporting in UK’s Yellow Card Scheme and discussed how Compliance with Ethical Standards patient reporting may provide a positive complementary contribution to that of healthcare providers; however, the Funding This study was funded by a Japanese government-based combination of reports from patients and healthcare pro- Grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology, Tokyo, Japan (Grant KAKENHI: 26460215). The viders, when used for the purposes of signal detection funders had no role in study design, data collection and analysis, through disproportionality analysis, may result in the loss decision to publish, or preparation of the manuscript. of some information [31, 32]. Our findings in the US lead to similar conclusions to these previous studies in Euro- Conflict of interest Tadashi Toki was employed by Daiichi Sankyo Co. Ltd during the study period. 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Direct-to-consumer pharmaceutical advertising: Pharmacol. 2017;83(2):227–46. therapeutic or toxic? Pharm Ther. 2011;36(10):669–74. 39. Bergvall T, Noren GN, Lindquist M. vigiGrade: a tool to identify well-documented individual case reports and highlight systematic data quality issues. Drug Saf. 2014;37(1):65–77. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Drugs - Real World Outcomes Springer Journals

Spontaneous Reporting on Adverse Events by Consumers in the United States: An Analysis of the Food and Drug Administration Adverse Event Reporting System Database

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Medicine & Public Health; Pharmacotherapy; Pharmacology/Toxicology; Internal Medicine
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Abstract

Drugs - Real World Outcomes (2018) 5:117–128 https://doi.org/10.1007/s40801-018-0134-0 ORIGINAL RESEARCH ARTICLE Spontaneous Reporting on Adverse Events by Consumers in the United States: An Analysis of the Food and Drug Administration Adverse Event Reporting System Database 1 1 Tadashi Toki Shunsuke Ono Published online: 3 May 2018 The Author(s) 2018 Abstract Conclusions Our analysis of voluntary AE reports in the Background Voluntary reports on adverse events (AEs) US FAERS database has shown that voluntary reports submitted by consumers have been facilitated through the tended to include AEs related to subjective symptoms, as in MedWatch program in the United States (US), but few some previous studies on patient reporting in the EU. studies have described the characteristics of voluntary Voluntary reports by consumers seemed to be different reports. from ones by healthcare professionals in important aspects Objective The aim of this study was to reveal the charac- including demographics and reporting behaviors. These teristics of current voluntary reports on AEs reported by findings suggest that the heterogeneities should be consumers and healthcare professionals. addressed appropriately in using spontaneous reports. Methods We performed analysis on voluntary reports of AEs in the US Food and Drug Administration AE Reporting System (FAERS) database submitted in 2016. Key Points We compared reports by consumers with those by health- care professionals. The number of voluntary adverse event (AE) reports Results The number of voluntary reports by consumers has by consumers, which reflect concerns and increased since 2013 in the US. Reports by consumers were restrictions specific to consumers, has apparently different from ones by health professionals in several increased since the introduction of the ‘consumer- important aspects such as demographics and outcomes of friendly’ reporting form FDA3500B in 2013, patients, AEs, and suspect drugs. The proportion of reports accounting for about half of the total AE reports in on female patients and on disability as a patient outcome the second quarter of 2016. were higher in reports by consumers than in those by healthcare professionals. Consumers more frequently Reports by consumers were different from ones by health professionals in important aspects such as reported concomitant drugs compared with healthcare demographics and outcomes of patients, AEs, and professionals. Time to report varied among the occupations suspect drugs. Report completeness and time-to- and depending on seriousness of outcomes. report also varied depending on the occupation of reporters. Electronic supplementary material The online version of this Observed characteristics in spontaneous reporting in article (https://doi.org/10.1007/s40801-018-0134-0) contains supple- mentary material, which is available to authorized users. the US should be considered in using AE reports in pharmacovigilance activities, especially when AE & Shunsuke Ono reports are compared with ones in different shun-ono@mol.f.u-tokyo.ac.jp countries/regions. Laboratory of Pharmaceutical Regulation and Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan 118 T. Toki, S. Ono types and variations of data sources, because the internal 1 Introduction and external validity of analyses using the databases totally Recent changes in pharmaceutical markets and regulations, depend on them. Regarding that perspective, however, spontaneous reports have attracted less attention than including introduction of new accelerated approval path- ways [1–3], new lines of therapies with innovative phar- obligatory reports from the industry. There are a couple of studies on spontaneous reports by nurses and physicians in macological mechanisms from molecular-targeted drugs to immune checkpoint inhibitors and to cell therapies, and locally established databases of AE reports, but there have been few analytical studies focusing on spontaneous growing expectations from patients for new therapies under development, have prompted regulators and industries to reporting by consumers in the US [22–25]. In the European Union (EU), patient-oriented reporting has grown gradu- introduce new drugs faster and more efficiently [4]. These ally since the 2000s, and current situations have been trends have made postmarketing pharmacovigilance more described in previous studies [25–30]. In one study it was important than ever [5]. The United States (US) Food and concluded that patient reporting successfully comple- Drug Administration (FDA) Adverse Event (AE) Report- ing System (FAERS) database, one of the largest phar- mented reporting by healthcare professionals, and the conclusion was consistent with that of a study in the UK macovigilance databases, plays a key role in both collecting and providing data on drug-related AEs. In the [31, 32]. Another study using the database of the Dutch Pharmacovigilance Center Lareb showed that patients US, the FAERS database gives the FDA critical signals and a decision basis to take regulatory actions such as ordering report clinical information at a similar level to healthcare professionals. labeling changes in the warning and/or precaution sections In this study, we aimed to identify the characteristics of to improve drug use in markets [6, 7]. Epidemiologists recent voluntary reports submitted by consumers and worldwide use the database to detect novel drug-related compare them with those by healthcare professionals. We safety events, to identify possible mechanisms of AEs, and discussed what backgrounds have led to the observed dif- to explore efficient methods to detect potential drug-related ferences, especially focusing on how information available AEs [8–14]. The database has been used beyond the realm of safety. For example, several researchers have recently on AEs could influence reporters’ attitudes to AE reporting. studied drug–drug interactions with new approaches using the FAERS database, which could lead to discovery of 2 Methods promising new concomitant uses of drugs in certain ther- apeutic areas [15, 16]. We analyzed the FAERS database and examined the For all purposes, the integrity of databases is a critical condition for users to obtain unbiased conclusions. Under- reports submitted by consumers and healthcare profes- sionals. We showed the transition of the numbers of vol- reporting has been a serious issue that afflicts pharma- untary reports in the US (Fig. 1), and conducted several covigilance activities worldwide [6, 17]. Previous studies showed that under-reporting was caused by many factors, descriptive analyses to reveal the characteristics of current voluntary reports. All the descriptive analyses were based including inevitable dependency on reporters volunteering incentives and lack of awareness of how to use public on the reports (25,814 reports) in the first and second quarter of 2016, and the analyses related to primary suspect reporting systems, or even their existence [18, 19]. A practical approach to improve the situation of under-re- drugs were based on reports for which primary suspect drugs were registered in the SIDER4.1 database. porting is to publicize the reporting system and to encourage not only healthcare professionals but also the 2.1 Food and Drug Administration (FDA) Adverse consumers who actually experience AEs, and their fami- Event (AE) Reporting System (FAERS) Data lies, to submit AE reports to the FDA. The FDA has also Preparation made efforts to reduce undesirable disproportionality (e.g., over- or under-representation of specific populations) in the FAERS. To alleviate these concerns, the FDA has contin- We used the JAPIC AERS database, comprising the FAERS database cleaned by the Japan Pharmaceutical uously expanded the MedWatch program for more than 20 years. The FDA introduced the first voluntary reporting Information Center (JAPIC), which was provided for our study under a collaborative research contract. During data form FDA3500 in 1993 and the form FDA3500B in 2013, a voluntary consumer-friendly reporting form, to encourage cleaning, JAPIC eliminated redundant cases, adjusted units to make them uniform, mapped drug names onto their drug reporting by patients [20, 21]. It is important for database users to acknowledge basic name dictionary, and refreshed preferred terms (PTs) in the Medical Dictionary for Regulatory Activities (MedDRA, characteristics of spontaneous safety databases, including ver.19.1) terminology. Spontaneous Reporting on Adverse Events in the US 119 Fig. 1 Changes in the number of voluntary reports by consumers and which suggests that most UNs after Q3 of 2013 are consumers using healthcare professionals. The bar graph shows the number of the FDA3500B form. AE adverse event, CN consumer, MD physician, quarterly reports. The ‘only-for-consumer’ FDA3500B form was OT other healthcare professional, PH pharmacist, UN unknown introduced in 2013, and AE reports by unknown occupation reporters occupation reporter (UN) have increased sharply since the 3rd quarter (Q3) of 2013, 2.2 Definition of Reporters reports by ‘unknown occupation’ reporters. We used the following abbreviations for each type of reporter: CNs for We classified reporters into consumers, pharmacists, consumers, UNs for unknown occupation reporters (in- physicians, and other healthcare professionals according to cluding consumers using FDA3500B), PHs for pharma- the reporter’s occupation on the form. The main focus of cists, MDs for physicians, and OTs for other healthcare this research was to reveal the characteristics of voluntary professionals. reports (e.g., demographics, background diseases, type of AEs, time-to-report) by consumers in the US and compare 2.3 Additional Data Collection them with reports by healthcare professionals. For this aim, we looked at both the voluntary reports by those who To determine whether AEs in a report were already known clearly identified themselves as ‘consumers’ in the classical (i.e., written in the labels at the time of AE reporting), we voluntary reporting form FDA3500 (Group 1) and the used the SIDER database on marketed chemical medicines voluntary reports in form FDA3500B that lacked the and related adverse drug reactions from drug labels [33]. occupation item because it is intended for use by con- SIDER used the MedDRA dictionary to extract side effects sumers (Group 2). The form FDA3500B, which was from labels. The results of this mapping are available under released in 2013 to facilitate consumers’ voluntary reports, a Creative Commons Attribution-Noncommercial-Share has the same items as FDA3500 except for occupation. The Alike 4.0 License. We downloaded the data from the instructions in FDA3500B are easier for consumers to SIDER website on April 18, 2017. Because SIDER version understand, even for first-time users. 4.1 was released on October 21, 2015, we treated the Although the reports in both groups (1 and 2) were adverse drug reactions (ADRs) included in SIDER 4.1 as supposed to be submitted by consumers, another research known ADRs. If one of the AEs in a report was a known question would be on whether the users of the form ADR for the primary suspect drug in the report, we con- FDA3500 might be different from the users of the form sidered that the report had known ADR(s). We collected FDA3500B in some demographic traits as well as AEs and data on safety labeling changes from monthly safety drugs reported. However, the current dataset publicly labeling changes on the FDA’s MedWatch websites [34]. available from FAERS does not have a code showing in Using the archival data we also obtained data on how many which form the report was submitted and it was impossible times the primary suspect drug experienced safety labeling to compare Groups 1 and 2 directly. We therefore tagged changes in the black box warning, warning, and/or pre- Group 1 as the reports by ‘consumers’ and all the reports caution sections. that lacked reporter’s occupation, including Group 2, as 120 T. Toki, S. Ono 2.4 Data Analysis studied decades. Significant proportions of reports in Q1 and Q2 of 2016 were made by PHs (44%) and UNs (37%). The completeness of reports is a quality indicator that Given the fact that 72% of voluntary reports in 2005 were reflects the characteristics of reporters and environments, made by healthcare professionals, including PHs and MDs, including reporters’ motivation for AE reporting. We the contribution of consumers has been steadily on the rise. assessed the completeness in reports by different types of reporters for the following items: patient sex, patient age, 3.2 Contents of Reports: Demographics, patient weight, indications, event date, route of primary Indications, Suspect Drugs, AEs, and Outcomes suspect drug administration, secondary suspect drug(s), and concomitant drugs. We examined the time to report (i.e., The sex ratio of patients was different between the repor- the time between AE occurrence and submission of the AE ters (Fig. 2a). Reports by consumers tended to have AEs report to the FDA) because it is an interesting indicator observed in female patients, while reports from healthcare reflecting reporters’ responsiveness to AE reporting. This professionals did not show such an imbalance. The average indicator reflects various reporting conditions, including patient age was 55.4, 50.5, 56.9, 52.0, and 52.0 years for carefulness, to determine the cause of AEs and priority of reports by CNs, UNs, PHs, MDs, and OTs, respectively AE reporting, which might be especially notable for (Fig. 2b). Patient outcomes were different according to the healthcare professionals. We analyzed the time to report occupation of reporters (Fig. 2c). The proportion of dis- from two aspects. First, we examined possible associations ability cases was much higher in reports by CNs and UNs between the time to report and whether the AEs were than those by healthcare professionals. As expected, reports known at the time of AE occurrence in all cases, ones with by MDs were likely to include hospitalization much more serious outcome, or ones with non-serious outcome. This frequently than those by the other occupations. would offer clues to how responsiveness differs between Typical profiles of AE reports by each occupation were the reporters facing different levels of uncertainties. Sec- described in terms of AEs, primary suspect drug, and ond, we examined time to report by stratifying by whether indication. The types of AEs frequently included were not the primary suspect drug had experienced safety labeling much different among the reports from different occupa- changes, which may raise public awareness of drugs and tions (Table 1). Fatigue, headache, and nausea were AEs and affect healthcare professionals and consumers in reported frequently in the reports from PHs and OTs. different ways. Regarding primary suspect drugs, sofosbuvir was most We used PostgreSQL version 9.3 and Python version 2.7 frequently observed in the reports by CNs, PHs, and OTs for data extraction. Chi square test and Wilcoxon rank-sum (Table 2). test were used for inter-group comparisons. The signifi- Reported indications reflected the indications of primary cance threshold was set at p = 0.05 in all statistical suspect drugs, although indication was missing in most of analyses. the reports (Table 3). In reports with the data available, hepatitis and rheumatoid arthritis were the top two indi- cations reported by CNs, PHs, and OTs. Interestingly, 3 Results indications in the reports by CNs were different from those by the UNs, although it was supposed that both CNs and 3.1 Trend in Spontaneous AE Reporting UNs indicate consumers, as discussed above. The users of FDA3500 and the users of FDA3500B might therefore be From Q4 of 1997 through Q2 of 2016, 482,938 voluntary different in background. reports were submitted to the FDA, 69,267 by consumers, 175,675 by unknown occupation reporters, 138,454 by 3.3 Report Completeness and Time to Report pharmacists, 40,668 by physicians, and 58,874 by other healthcare professionals. The total number of voluntary Completeness of reports differed among the occupations reports increased from 2251 in Q4 of 1997 to 13,866 in Q2 [Online Resource 1, see electronic supplementary material of 2016, with the upward trend especially noticeable since (ESM)]. Patient sex and age were reported in most of the Q3 of 2013 when the consumer-friendly form FDA3500B reports. For the other items, the reporting rate varied by the became an option for consumer reporting (Fig. 1). Because type of reporters. Among them, concomitant drug(s) were the number of reports from consumers using the form reported more often in the reports by CNs and UNs than in FDA3500 diminished after 2013 (CN in Fig. 1), the those by PHs, MDs, and OTs. observed trend indicates that UN reporters after 2013 Reports by OTs had the shortest time to report with a mostly consisted of consumers who used FDA3500B. The median time of 5 days (Fig. 3), while reports by CNs contributions of various reporters have changed in the showed the longest time to report with a median time of Spontaneous Reporting on Adverse Events in the US 121 Fig. 2 Distribution of reports grouped based on patient sex (a), age every 10 years (b), and patient outcome (c). The definition for seriousness of patient outcome in this paper followed the description in the International Conference on Harmonization (ICH) E2 guideline. CA congenital anomaly, CN consumer, DE death, DS disability, HO hospitalization—initial or prolonged, LT life-threatening, MD physician, NS non-serious, OS other serious (important medical event), OT other healthcare professional, PH pharmacist, RI required intervention to prevent permanent impairment/damage, UN unknown occupation reporter. *p \ 0.05 (Chi square test for the ratio of reports with a female patient to those with a male patient vs CN); p \ 0.05 (vs UN) 22 days. The time to report by CNs seemed longer than However, the time to report in consumers’ reports was not that by UNs, suggesting that consumers may use the two affected by seriousness of outcomes. CNs submitted AEs reporting forms differently, or that the users of each form where the primary suspect drug had experienced safety are somewhat different. The median time for PHs, MDs, labeling changes in the black box warning sections earlier and UNs was 9.5, 15, and 15 days, respectively. Time to than other AEs (Online Resource 3, see ESM). In contrast, report was longer in serious cases than in non-serious cases PHs and OTs submitted the AEs earlier when the primary except for the reports by MDs. suspect drug had labeling changes in the warning or pre- We also examined how time to report varied among the caution sections, but not in the black box warning. occupations depending on whether the AE was known or not, and on whether the primary suspect drug had experienced safety labeling changes (Fig. 4, Online Resource 2 and 3, see 4 Discussion ESM). In all the reports by PHs, the time to report for known AEs was shorter by 1 day (median) than that for unknown Our analysis showed that consumers’ reports, which have AEs. In the reports with serious outcome, PHs reported accounted for a significant portion of recent increases in the known ADRs slowly, and OTs reported them rather fast. number of voluntary reports, seem to have information that 122 T. Toki, S. Ono Table 1 Top 10 MedDRA preferred terms (PTs) for AEs ranked by the most frequently reported by each type of reporter CN No. of UN No. of PH No. of MD No. of OT No. of reports reports reports reports reports 1 Headache 43 Headache 404 Fatigue 808 Nausea 54 Fatigue 195 2 Nausea 42 Fatigue 376 Headache 622 Product 54 Headache 159 substitution issue 3 Dizziness 37 Dizziness 347 Nausea 417 Pyrexia 48 Nausea 126 4 Dyspnea 37 Nausea 345 Diarrhea 304 Drug ineffective 43 Diarrhea 77 5 Fatigue 37 Drug 316 Rash 221 Diarrhea 41 Rash 63 ineffective 6 Diarrhea 34 Pain 313 Dizziness 189 Fatigue 38 Product 62 substitution issue 7 Pain 27 Arthralgia 312 Insomnia 181 Dizziness 33 Dizziness 54 8 Asthenia 23 Blood glucose 296 Dyspnea 178 Seizure 33 Insomnia 47 increased 9 Vomiting 22 Pain in 288 Vomiting 178 Vomiting 33 Vomiting 46 extremity 10 Chest 19 Insomnia 257 Pruritus 138 Headache 32 Drug ineffective 38 pain AE adverse event, CN consumer, MD physician, OT other healthcare professional, PH pharmacist, UN unknown occupation reporter Table 2 Top 10 primary suspect drugs ranked by the most frequently reported by each type of reporter CN No. of UN No. of PH No. of MD No. of OT No. of reports reports reports reports reports 1 Sofosbuvir 71 Metformin 704 Sofosbuvir 1250 Cisplatin 55 Sofosbuvir 345 2 Ritonavir 26 Levonorgestrel 314 Everolimus 366 Temozolomide 41 Ribavirin 78 3 Metformin 22 Levofloxacin 287 Warfarin 245 Cyclophosphamide 39 Capecitabine 64 4 Capecitabine 16 Ciprofloxacin 201 Capecitabine 188 Carboplatin 31 Everolimus 52 5 Everolimus 12 Canagliflozin 129 Ribavirin 180 Lamotrigine 28 Emtricitabine 45 6 Ribavirin 12 Etonogestrel 101 Ustekinumab 148 Canagliflozin 17 Tenofovir 45 disoproxil fumarate 7 Apixaban 11 Sofosbuvir 93 Rivaroxaban 125 Bicalutamide 15 Methotrexate 29 8 Deferasirox 11 Sodium 90 Dasatinib 106 Cytarabine 15 Tacrolimus 28 chloride 9 Ciprofloxacin 10 Rivaroxaban 80 Deferasirox 104 Dexamethasone 14 Ivacaftor 27 10 Hydrochlorothiazide 10 Lamotrigine 76 Tobramycin 104 Sofosbuvir 14 Temozolomide 25 CN consumer, MD physician, OT other healthcare professional, PH pharmacist, UN unknown occupation reporter is not necessarily provided by healthcare professionals. system through the MedWatch program in 2013 [20, 21]. Differences were observed not only in AEs, suspect drugs, These efforts apparently have achieved an excellent out- and health outcomes, but also in reporting quality and come in enhancing voluntary reporting. Figure 1 indicates behaviors such as report completeness and time to report. that the total number of voluntary reports in the US has In the US, the FDA has facilitated voluntary reports by increased, especially since 2013, and that consumers seem consumers through several activities such as the release of to have contributed to that increase. This was probably due a new consumer-friendly reporting form FDA3500B and to encouragement and increased public recognition that the refurbishment of the interface of its online reporting patients, as well as healthcare professionals, could report Spontaneous Reporting on Adverse Events in the US 123 Table 3 Top 10 indications ranked by the most frequently reported by each type of reporter CN No. of UN No. of PH No. of MD No. of OT No. of reports reports reports reports reports 1 Hepatitis C 131 Missing 2332 Missing 1312 Missing 342 Missing 479 2 Missing 124 Urinary tract 153 Hepatitis C 688 Type 2 diabetes 21 Hepatitis C 246 infection mellitus 3 Atrial 14 Sinusitis 151 Chronic 372 Hepatitis C 18 Chronic hepatitis 90 fibrillation hepatitis C C 4 Hypertension 10 Contraception 132 Atrial 368 Diabetes mellitus 13 Product used for 68 fibrillation unknown indication 5 Breast cancer 9 Hypertension 103 Product used for 345 Chronic hepatitis 12 HIV infection 55 unknown C indication 6 HIV infection 8 Pneumonia 87 Neoplasm 175 Contraception 9 Cystic fibrosis 50 malignant 7 Product used for 8 Depression 84 Cystic fibrosis 149 Rhinitis allergic 9 Rheumatoid 25 unknown arthritis indication 8 Anxiety 7 Bronchitis 72 Hypertension 146 Atrial fibrillation 8 Hypertension 22 9 Pain 7 Pain 69 Pain 145 Attention deficit/ 8 Chronic myeloid 20 hyperactivity leukemia disorder 10 Rheumatoid 7 Hepatitis C 65 HIV infection 122 Epilepsy 8 Attention deficit/ 18 arthritis hyperactivity disorder CN consumer, MD physician, OT other healthcare professional, PH pharmacist, UN unknown occupation reporter Fig. 3 Distribution of time to report stratified by each reporter (a) and the seriousness of patient outcome (b). Boxplot with whiskers with maximum 1.5 interquartile range. Any data not included between whiskers are plotted as an outlier with a dot. If the value for the first quartile is zero, the box is not shown. CN consumer, MD physician, OT other healthcare professional, PH pharmacist, UN unknown occupation reporter. *p \ 0.05 (Wilcoxon rank-sum test) AEs directly to the FDA, especially using the online periods is a problem. For data mining purposes, changes in reporting form. the quality of information must be considered in statisti- The increase in the number of reports is beneficial to cally rigorous ways [17, 35]. Besides the statistical aspects, overall pharmacovigilance activities, but it inevitably safety authorities and drug companies need to decide draws experts’ attention to increasing heterogeneity in the whether and how we should prioritize concerns for specific safety database due to diversified reporting sources. safety issues presented by diverse reporters in current Needless to say, statistical inconsistency between different public health needs. All these issues make it necessary to 124 T. Toki, S. Ono Fig. 4 Distribution of time to report grouped by whether a report included ‘known’ drug- related AEs for all reports (a), reports with serious outcome (b), or reports with non-serious outcome (c). Boxplot with whiskers with maximum 1.5 interquartile range. Any data not included between whiskers are plotted as an outlier with a dot. If the value for the first quartile is zero, the box is not shown. AE adverse event, CN consumer, MD physician, OT other healthcare professional, PH pharmacist, UN unknown occupation reporter *p \ 0.05 (Wilcoxon rank-sum test) clarify how consumers are different from traditional in patients. In contrast, healthcare professionals rarely reporters, mostly healthcare professionals, and also to test reported disability cases. This indicates that reports by whether reports from consumers who choose the new consumers can add information about AEs that may not be reporting form and routes are different from reports by emphasized by healthcare professionals, and this is con- consumers who choose (or chose) the traditional reporting sistent with a recent systematic review of the literature on form. patient reporting [38]. Our analysis identified several interesting features in US Report completeness has been considered an indicator voluntary reports. We found some disparities in patient sex for well documented AE reports and used for data mining reported by different occupations. Previous studies showed in the World Health Organization’s pharmacovigilance that female patients had a 1.5- to 1.7-fold greater risk of database VigiBase [35, 39]. A recent paper showed that developing an ADR, which might be caused by sex dif- voluntary reports have a higher level of report complete- ferences in pharmacological response [36, 37]. Another ness than do reports from drug companies: the complete- recent study presented the same sex disparity and also ness of all four items (sex, age, event date, and medical showed that healthcare professionals tended to report terms) was 86.2% in serious reports submitted directly to ADRs of male patients more than other types of reporters the FDA (i.e., voluntary reports), as compared with 40.4% did [28]. Our results indicate that consumers were more in manufacturer-expedited reports and 51.3% in manufac- likely to report AEs of female patients than were healthcare turer periodic reports, in 2014 [40]. We examined three professionals (Fig. 2), which was concordant with the items (i.e., event date, indication, and route of primary findings of previous studies. suspect drug) for which data are frequently missing in the Regarding reported patient outcomes, we found that FAERS database, and other important items including sex, consumers were likely to report AEs that caused disability age, and weight. The report completeness rates for these Spontaneous Reporting on Adverse Events in the US 125 items were almost the same in reports from different median time to report AEs by any reporter in the US was reporters, but some findings suggest possible differences in shorter than that in the EU. These differences in time to reporters’ interest and environment. For example, con- report are likely to reflect differences in reporting path- sumers’ reports lack the event date more often than do the ways: the voluntary AE reports in this research were other reports (Online Resource 1, see ESM). This may be directly submitted to the FDA, while some reports in the unsurprising, however, because AEs are detected, recorded, EU arrived at the authority via companies or other regu- and reported retrospectively based on the records and/or latory agencies. Different reporting times may also be memories available to the reporters. The fact that con- influenced by different cultures and histories surrounding sumers showed the longest time to report with a median the reporting systems and use of drugs, such as publicity time of 22 days (Fig. 3) may support the finding. around medicinal products, as a previous report suggested The number of concomitant drugs may reflect reporters’ [43]. With respect to suspect drugs, Table 2 indicates that availability of information, and how meticulous the MDs report AEs of oncologic injection drugs (e.g., cis- reporters are within real-world constraints. We found that platin and carboplatin) but consumers do not, which sug- consumers reported more concomitant drugs than did other gests that MDs and consumers report different AEs in reporters (Online Resource 1, see ESM). Our preliminary different settings, and may explain our observation (at least analysis showed that the number of concomitant drugs did partly) that time to report was much shorter in MDs than in not correlate with report completeness for any other items, consumers. It is worthwhile investigating whether this suggesting that this would not be a quality measure for reflects differences in the publicity and maturation of the general purposes. AE reporting system between the two regions. In general, consumers are thought to have less access to It was also shown that time to report by consumers was information on drug-related AEs in drug labels than do longer than that by pharmacists and other healthcare pro- healthcare professionals. Consumers do not have expertise fessionals, and almost equal to that by physicians (Fig. 3a). in pharmacovigilance activities, either. We had expected Comparisons between serious and non-serious cases that previous knowledge about AEs would affect reporting showed that time to report was longer in serious cases than behaviors differently for consumers and healthcare pro- in non-serious cases except in the reports by physicians fessionals, but our analysis using all the reports did not (Fig. 3b). With regard to whether the AE(s) were already show a clear difference between the two groups (Fig. 4a). written in the labels, interesting differences were observed This is basically in line with a conclusion in a previous between healthcare professionals in reports with serious report that patients can make causality assessment based on outcome(s) (Fig. 4b). Safety labeling changes of primary the available information [31, 32]. We further examined suspect drugs were associated with the time to report of healthcare professionals but not with those of consumers serious ADR cases and found that known ADRs were reported more slowly than unknown ADRs by PHs, and (Online Resource 3, see ESM). Time to report was asso- vice versa by OTs (Fig. 4b). This suggests differences ciated with which section of labeling (i.e., black box seem to exist among healthcare professionals. warning, warning, or precaution) had been revised, but in Histories of labeling revisions were associated with somewhat complicated ways. Interestingly, pharmacists observed differences between consumers and healthcare and other healthcare professionals tended to report earlier professionals in what and how they are likely to report the primary suspect drug for which safety labeling changes (Online Resource 2 and 3, see ESM). A possible expla- occurred in the warning or precaution sections, but not in nation is that healthcare professionals, and MDs in par- the black box warning. ticular, are less likely to be influenced by prior information Causalities behind these findings on time to report are about risk and/or more likely to adhere to their own complex and beyond our scope, but they probably reflect judgement than are consumers. However, it is difficult to diversities in the environment where reporters come to discuss the role of prior information and environment experience and/or be aware of AEs and decide to report based solely on our findings, because there are many AEs to the authority. Some consumers may have difficul- confounding factors. The issuance of regulatory alerts, for ties in reporting their own AE immediately after their example, is a possible confounder that has been investi- recovery, and need to take time to learn how to report AEs gated intensively in many studies [41, 42]. even when they intend to do so. Physicians, who com- Time to report is an interesting measure of promptness monly struggle with time conflicts on a daily basis, may in reporting and may help to describe reporting behaviors. face tradeoffs between voluntary and mandatory reporting. A recent study in the EU showed that median time to report Causal determination for AEs did not seem to play a crit- an ADR was approximately 30 days in spontaneous ical role as shown in Fig. 4 and Online Resource 3 (see reports, regardless of whether it was reported by patients or ESM). This is in line with a previous report that some healthcare professionals [28]. As shown in Fig. 3a, the consumers may be able to identify suspected ADRs 126 T. Toki, S. Ono adequately [31, 32]. To improve efficiency and respon- reporters’ occupations made it difficult to extract data from siveness in the current reporting system, we need to con- ‘real’ consumers. There are no official rules and/or prin- sider real-world mechanisms of reporting behaviors. For ciples on how to handle consumers’ reports in publication example, we need to examine the possible influence of and data mining, and our analysis had to be done under communications such as ‘Dear Healthcare Provider’ letters, such uncertainties. Our analysis did not cover mandatory which are expected to have substantial impacts on report- reports, which limits the generalizability of our results. A ing behaviors [41, 42]. significant portion of AE reporting is done as mandatory Our analysis provided several clues to the heterogeneity reporting, and drug companies play a key role in it. in reports from consumers, which were conveyed in one of Healthcare professionals choose reporting route(s) consid- the two different forms: the traditional form FDA3500 ering types and seriousness of AEs, applicable rules, and (tagged as ‘CN’ in this paper) and the new form many other factors including opportunity costs of report- FDA3500B (tagged as ‘UN’). It is apparently the latter ing. These considerations affect how healthcare profes- form that has contributed to the recent increase in the sionals report AEs voluntarily. Further studies are needed number of AE reports. Although the traditional form users to shed light on such broader aspects and examine the and the new form users were similar in some aspects (e.g., system as a whole. concomitant drugs, report completeness), they were apparently different in other important aspects including reported outcomes and indications, and time to report. It is 5 Conclusion quite natural that consumers use forms differently when a new reporting form and/or route is added to traditional Our analysis of voluntary AE reports in the US FAERS forms/routes, and this might be exactly what regulators database has shown the characteristics of spontaneous intended to facilitate. Our results suggest that database reporting in the US. Voluntary reports tended to include users have to be careful about such heterogeneities when AEs related to subjective symptoms, as in some previous combining or pooling reports made using the different studies on patient reporting in the EU. Voluntary reports by forms, even though they were all submitted by consumers seemed to be different from reports by health- ‘consumers.’ care professionals in demographics and outcomes of Finally, we can discuss our findings with reference to patients, and suspect drugs. They were also different in previous studies in the EU. As discussed above, the aver- report completeness and time to report, which may reflect age time to report in the US was much shorter than that in concerns and environments that are specific to each type of the EU, which may reflect the extent of differences in reporter. Consumers’ choice of voluntary reporting forms regulations and reporting pathway(s) [28]. Reporting may be worth studying further. These findings suggest that behaviors in consumers, including promptness to report, the heterogeneities should be addressed appropriately when may be affected by marketing environments such as direct- using spontaneous reports, especially in the context of to-consumer advertising [43]. Irrespective of these differ- international comparison. ences between the US and European countries, we found Acknowledgements We would like to thank Japan Pharmaceutical that consumers’ reports in both regions are similar in some Information Center (JAPIC) for permitting our use of the JAPIC important aspects. For example, consumers in both regions AERS database under a collaborative research contract. We would tend to report subjective symptoms such as headache, like to thank Editage (http://www.editage.jp) for English language fatigue, and nausea [28]. Avery et al. investigated patient editing. reporting in UK’s Yellow Card Scheme and discussed how Compliance with Ethical Standards patient reporting may provide a positive complementary contribution to that of healthcare providers; however, the Funding This study was funded by a Japanese government-based combination of reports from patients and healthcare pro- Grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology, Tokyo, Japan (Grant KAKENHI: 26460215). The viders, when used for the purposes of signal detection funders had no role in study design, data collection and analysis, through disproportionality analysis, may result in the loss decision to publish, or preparation of the manuscript. of some information [31, 32]. Our findings in the US lead to similar conclusions to these previous studies in Euro- Conflict of interest Tadashi Toki was employed by Daiichi Sankyo Co. Ltd during the study period. 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Drugs - Real World OutcomesSpringer Journals

Published: May 3, 2018

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