In this comparative study, we examined the extent to which the healthcare DB claims captured the safety profile of eribulin through the comparison of patient characteristics, status of drug use, and AE incidence in patients treated with eribulin with the previously conducted PMS of eribulin in Japan . The results demonstrated that, generally, the patient demographics, clinical characteristics, status of eribulin use, concomitant therapy use, and AE incidence based on the data from the DB and PMS were comparable in the pharmacoepidemiological investigations of eribulin.
For most of the AEs observed during eribulin administration, the occurrence was comparable based on the data from the DB and PMS. This was particularly notable for interstitial pneumonia, peripheral neuropathy, and anemia. The occurrence of AEs such as nausea, neutropenia, stomatitis, and alopecia varied between the two datasets. Overall, the AEs that were consistent between the DB and PMS data were symptomatic and may have required hospital treatment. However, more frequent nausea and stomatitis and less frequent alopecia were reported in the DB than the PMS. Such differences in AE incidence may have been attributable to the differences in the treatment of patients between the two datasets. For example, more patients in the DB received concomitant chemotherapy than in those in the PMS data (16.9% vs. 7.7%) and a slightly higher dose of initial eribulin (1.4 mg/m2 vs. 1.3 mg/m2). The differences in AE incidence also indicate that the diagnosis code for nausea and stomatitis were entered in the DB, for reimbursement purposes, indicating that treatments were required or prophylactic therapy was administered. AEs such as alopecia may have been less frequently entered into the DB when no treatment was required. Patients with moderate-to-severe but asymptomatic neutropenia may not have been diagnosed unless a blood test was performed. In addition, even if a patient was diagnosed with neutropenia, treatment may not have been administered unless required. In contrast, in the PMS data, neutropenia was determined based on the neutrophil count collected for the study; thus, regardless of symptoms, any occurrences of neutropenia were captured. Using the limited laboratory data available in the DB (n = 79), we further defined neutropenia as neutrophils < 1000 to 500/mm3 (Grade 3) or < 500/mm3 (Grade 4) in accordance with the Common Terminology Criteria for Adverse Events v3.0, when such an event had been recorded at least once, between the day after the start of eribulin administration and 14 days after the end of eribulin administration. Subsequently, the result was then compared to Grade 3 or 4 neutropenia from the PMS data, and small discrepancies of 43.04% and 59.83%, respectively, between the DB and PMS data, were observed. Based on these findings, PMS may be more appropriate for the collection of data on symptoms, including those that may not necessarily require treatment. To precisely capture AEs such as neutropenia, the definition of events based on their severity should also be carefully considered when using the MDV DB. As recommended in the guidelines for database research [6, 7], the use of an appropriate DB based on the purpose, with the original objective of the data source in mind, is essential. A health claims database may be particularly suitable for capturing events leading to reimbursements, but not for events affecting a patient’s quality of life. Thus, the decision on whether to conduct a PMS or to use an existing DB, based on the safety events to be assessed, is important.
In this study, use of the DB enabled assessments of the trends in drug use and AE incidence; we observed an increasing trend in the number of eribulin administrations and a decreasing trend in the use of concomitant hormone therapy with eribulin and AEs, such as anemia and pyrexia, over 5 or 6 years. The increased number of eribulin administrations and the decreased incidence of AEs may be because physicians have become more capable in the management adverse drug reactions, including the prevention of AEs. Furthermore, the use of concomitant hormone therapy may have decreased owing to the accumulated experience obtained by physicians of the administration of eribulin as a single agent. There may also have been a shift in the type of patient administered eribulin, from patients with hormone receptor-positive breast cancer to those without (patients with triple-negative status account for 18.4% of patients in the early post-marketing phase of eribulin , and patients with triple-negative status account for 25.1% of patients among those with HER2-negative cancer in the subsequent post-marketing phase ). Overall, the experience obtained by physicians of the administration of eribulin may be a common reason behind these three trends in our results.
Although moderately comparable results can be obtained from both the MDV DB and PMS data, the PMS is associated with an increased time and cost burden [3, 7] as previously stated. PMS and DB are non-interventional studies, and conducting a PMS, which has a prospective design, requires site contract, study monitoring, inquiries, and data entry by competent persons. There is a high cost and time requirement associated with this, even when the observational period is only a few months. Studies using a DB, which are of a retrospective design, take a shorter time to complete, and are relatively inexpensive. Biases are another issue in PMS. PMS exhibits strength in “all-case surveillance”; however, the data are not necessarily entered on time at the study sites, which results in under-reporting (recall bias) . PMS does not necessarily cover “all cases” when the patients and study sites are selected by physicians and sponsoring pharmaceutical companies, respectively (selection bias). If the drug safety can be evaluated by using the existing secondary data, the study can be conducted in a cost- and time-efficient manner, and the results obtained may be less biased. This would lead to the acquisition of data that are more organic and reflective of the real-world perspective. In addition, a DB-based study enables the assessment of long-term trends, with the retention of a large sample size. The PMS-based study, in contrast, has limits on both the time period and sample size. The DB-based studies have the following inherent limitation that makes it impossible to detect events pertaining to prophylaxis: limited availability of information to define target events. As these studies are, for the most part, retrospective, the time lag that occurs before the collected data are reflected in the database is another potential limitation. However, the biases vary depending on the target disease and drug.
Post-marketing safety assessments using DB and PMS data have both the aforementioned advantages and disadvantages. Our results suggest that MDV DB, instead of conducting PMS, can be used for the safety assessment of eribulin, especially for events that have triggered reimbursement. In addition, it should be noted that some AEs, such as neutropenia, alopecia, nausea, and stomatitis, may be under- or over-reported in the MDV DB, implying that both types of post-marketing studies are complementary in nature.
The coverage of patients in the DB depends on the target disease. We targeted patients with breast cancer treated with eribulin. The number of shipped eribulin vials from Eisai Co. Ltd. depicts a fair consistency with the number of administered eribulin included in the DB. Our findings can therefore be generalized to patients treated with eribulin in Japan during the study period.
Our study is associated with a few limitations. Selection bias was inevitable both in the PMS and the DB used for our study. As previously mentioned, the participating sites and the patients participating in the study for PMS were selected by the pharmaceutical company and the attending physicians, respectively. For DB, all data included in the MDV DB were provided by hospitals with advanced medical capabilities, where DPC/PDPS is employed. The results also required careful interpretation, and data availability was limited in the DB. The AEs were also defined based on the disease name entered as part of the data required for reimbursement purposes, serving as another limitation. In addition, the acquired results may vary depending on the definition employed, and prophylactic treatments could not be differentiated in the DB.