FormalPara Key Points

This is the first survey conducted among healthcare professionals in Japan to assess the effectiveness of materials created as additional risk minimization measures (aRMM).

The majority of pharmacists answered that they had explained how to take ixazomib citrate (IXA) to patients and that aRMM material was utilized at the time of the explanation.

Overall, the aRMM material appears to contribute to the appropriate use of IXA.

1 Introduction

In the risk management cycle of medicinal products, implementing activities and interventions to identify, prevent, or minimize the risks associated with a product and assessing the effectiveness of these activities is crucial [1]. As the objective of additional risk minimization measures (aRMMs) is achieved through the implementation of safety measures and the evaluation of their effectiveness, guidance on assessing the effectiveness of aRMMs has been established in Europe and the US [1,2,3]. A common method of aRMMs involves preparing and distributing educational materials for patients and healthcare professionals (HCPs). Multiple studies have been conducted on the effectiveness of these materials [4,5,6,7,8].

However, in Japan, although Japanese regulations indicate that the effectiveness of aRMMs should be evaluated at certain milestones [9], specific methods have not been established. To the best of our knowledge, no studies evaluating the effectiveness of aRMMs have been published since an exploratory survey was conducted for baloxavir marboxil in Japan [10]. To realize a more appropriate risk management cycle in Japan in the future, the pharmaceutical industry is interested in developing regulations and accumulating examples related to the evaluation of the effects of aRMMs.

Ixazomib citrate (IXA), a proteasome inhibitor, was approved in Japan in 2017 for the treatment of relapsed or refractory multiple myeloma (RRMM) in combination with lenalidomide and dexamethasone (IRD therapy). The dosing schedule for these three drugs is different; for IXA, one capsule should be taken under fasting conditions on days 1, 8, and 15. To promote understanding of the appropriate dosing regimen, dosing instructions for patients (aRMM material) describing the dosing schedule and precautions for administration have been prepared and distributed to patients via HCPs since its launch in Japan. Distribution methods include paper-based distribution to medical institutions via medical representatives and electronic posts on the websites of the regulatory authority and the marketing authorization holder. In this study, a survey was conducted to investigate whether the aRMM material is utilized to avoid medication errors in the use of IXA among patients, which can have significant impacts on patient safety.

2 Methods

2.1 Study Design and Respondent Selection

Given that drugs for IRD are prescribed and dispensed primarily in hospital settings in Japan, in-hospital pharmacists are mainly responsible for receiving and distributing the aRMM material and explaining the dosing of IXA in IRD therapy. This web-based cross-sectional questionnaire survey was conducted in Japan using the Nikkei Medical Online Panel, operated by Nikkei Business Publications, Inc. (Tokyo, Japan), with over 190,000 registered pharmacists as of September 2023 [11]. The survey was self-administered online. Participant recruitment and response collection was conducted from June 1, 2023, to June 9, 2023.

A total of 24,000 pharmacists registered for hospital work in the panel who were able to receive e-mails were invited to participate in the survey via e-mail and the portal site. At this step, the survey background and objectives, the contact information for questions, the intended use of data, and the proposed compensation were explained to the pharmacists. Pharmacists who consented to participate in the survey were provided with access to the web questionnaire and were tasked with answering it following the instructions. This survey targeted in-hospital pharmacists who have instructed the dosing of IRD therapy to patients with RRMM. Pharmacists who worked in pharmacy/drug stores or other non-hospital locations, had no experience of prescribing IXA for RRMM, or did not complete all of the questions in the questionnaire were excluded. Recruitment was terminated when the number of participants who completed all questions reached the planned sample size plus 10%. The screening results are shown in Fig. 1.

Fig 1
figure 1

Screening results. Note: Response rate = Pharmacists who consented to participate in this study/Targeted pharmacists; Cooperation rate = Pharmacists who completed the questionnaire/Pharmacists who passed the screening questions. IXA ixazomib citrate, RRMM relapsed or refractory multiple myeloma

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2.2 Outcomes

Generally, studies evaluating risk minimization measures assess different aspects of aRMM performance using a combination of process and outcome indicators. Process indicators include the impact on knowledge and behavioral changes in patients and HCPs, whereas outcome indicators are the ultimate measure of success, such as a decline in the frequency and/or severity of adverse events [12]. Although the ultimate purpose of aRMM material in this survey was to reduce accidental overdose and associated serious adverse events, observing a decline in overdose and related adverse event cases (i.e., outcome indicators) was difficult since the relevant information cannot be fully captured in existing data sources. Considering the importance of understanding regarding how to use IXA among HCPs and explaining it to patients to achieve the goal of aRMM material, this survey used process indicators to evaluate the effectiveness of the aRMM material.

The primary endpoint was the proportion of pharmacists who provided patients with the contents of the aRMM material, which is “to take 1 capsule of IXA each time on days 1, 8, and 15 under fasting conditions (how to take IXA).” The secondary endpoints were the proportion of pharmacists who had obtained the aRMM material and the proportion of pharmacists who understood the importance of explaining how to take IXA to patients.

2.3 Survey Methodology

A web-based anonymous survey questionnaire consisting of 18 close-ended single/multiple-choice questions in Japanese was developed. The questionnaire included questions on participating pharmacists, hospitals where pharmacists worked, the status of explaining to patients how to take IXA, aRMM material, and the appropriate use of IXA. Other exploratory questions (level of understanding of the risk management plan [RMP] for IXA, elements to look for in patient leaflets, and media preferences [paper/electric]) were also included. A complete list of the questionnaire items is provided in Supplementary Table 1, see the electronic supplementary material (ESM).

2.4 Statistical Analysis

A target sample size of 300 pharmacists (the final analysis population) was set. When n = 300, the two-sided 95% confidence interval for the response rate of the binary questionnaire had a maximum width of ± 5.7%. The analysis set included all pharmacists who met the eligibility criteria and answered all questions; therefore, no data were missing in the analysis set. For each question, the number and/or percentage of participants who responded to each answer option was calculated. Cross-tabulations were also performed between the participants' backgrounds and/or questions. Statistical analyses were performed using ASSUM version 5.9 (Japan Information Processing Service Co., Ltd., Tokyo, Japan).

3 Results

3.1 Participant Characteristics

Of the 24,000 pharmacists invited to participate, 1329 consented to participate in the survey, and 336 pharmacists passed the screening questions. Of these, 330 pharmacists who completed all questions were included in the analysis. The overall response rate (proportion of pharmacists who consented to participate in this survey out of the targeted pharmacists) was 5.5%, and the overall cooperation rate (proportion of pharmacists who completed the questionnaire out of those who passed the screening questions) was 98.2% (Fig. 1).

Descriptive characteristics of the study population are presented in Table 1. All responding pharmacists belonged to hospitals (no clinic pharmacists). Approximately half (47.0%) worked in hospitals with ≥ 500 beds. Over three-quarters (76.7%) of the respondents had ≥ 10 years of experience as a pharmacist, and most respondents (83.3%) had specific qualifications, including board-certified pharmacists in oncology pharmacies. The majority of respondents (57.9%) had dispensed IXA for RRMM in the past year.

Table 1 Characteristics of responding pharmacists (N = 330)
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3.2 Status of Informing Patients How to Take Ixazomib Citrate (IXA)

Of the analyzed population, 307 pharmacists (93.0%) answered that they informed patients on how to take IXA (Table 2). Of the 307 pharmacists, 102 (33.2%) answered that they had experience using the aRMM material when explaining how to take IXA. Of the 120 pharmacists with aRMM material who answered that they had explained how to take IXA to patients, 86 (71.7%) answered that they had used the aRMM material. Sixteen pharmacists (8.6%) answered that they had experience in using the aRMM material but had no experience in obtaining it. Pharmacists who fully understood the RMP for IXA tended to have more experience in using the aRMM material (n = 75, 70.7%) than pharmacists who had read but not fully understood (n = 131, 34.4%) or had not read the RMP (n = 101, 4.0%).

Table 2 Status of providing patients with instructions on how to take IXA and materials used (N = 307a)
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3.3 Status of Having Obtained the Additional Risk Minimization Measure (aRMM) Material

Overall, 124 pharmacists (37.6%) answered that they had experience in obtaining the aRMM material (Table 3). Pharmacists who belonged to cancer centers and other specialized institutions in cancer care (n = 6, 100.0%) or who had any qualifications related to cancer, such as board-certified oncology pharmacy specialists (n = 21, 71.4%) and board-certified pharmacists in palliative pharmacies (n = 32, 59.4%), tended to have a higher proportion of experience in obtaining the aRMM material. Access to the aRMM material was higher among pharmacists with recent dispensing experience within the past year (n = 191, 41.4%), 1–3 years (n = 73, 35.6%), and ≥3 years (n = 66, 28.8%). Pharmacists who fully understood the RMP for IXA (n = 75, 81.3%) tended to have more experience in obtaining aRMM material than those who had read but not fully understood (n = 138, 42.8%) or had not read the RMP (n = 117, 3.4%).

Table 3 Status of receipt of the aRMM material (N = 330)
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3.4 Level of Understanding of the Appropriate Use of IXA

Overall, 316 pharmacists (95.8%) answered that they knew how to take IXA. Regarding the importance of explaining this information to patients, 298 (90.3%), 30 (9.1%), 1 (0.3%), and 1 (0.3%) pharmacists answered “very important,” “probably important,” “less important,” and “not important,” respectively (Table 4).

Table 4 Understanding of the appropriate use of IXA and the importance of explaining it (N = 330)
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3.5 Exploratory Results

The elements most frequently selected as being important in the patient leaflets used to explain how to take IXA were “whether the text is easy to read for patients” (88.5%), “appropriateness of information volume” (70.3%), and “color printing” (13.0%) (Supplementary Table 2, see ESM) (as multiple responses were allowed, the total exceeded 100%). Regarding media preferences, more pharmacists answered “paper media” (76.4%) than “electronic media” (8.5%), and 15.2% answered “either is acceptable” (Supplementary Table 3, see ESM).

4 Discussion

This was the first survey among HCPs in Japan to evaluate the effectiveness of aRMM material. The results of this survey revealed that pharmacists explained how to take IXA to patients and that the aRMM material was utilized at the time of the explanation. As the environment for evaluating the effectiveness of aRMMs in Japan is not well established and the number of previous surveys is limited, this study may serve as a valuable reference for how such surveys should be conducted in Japan in the future.

Among the participants in this survey, no pharmacists belonged to clinics, and approximately half of them worked in hospitals with ≥500 beds. This indicates that our analysis population was an appropriate target for this survey, as IXA is dispensed mainly at designated cancer care hospitals, many of which are regional core hospitals or larger [13]. In addition, more than three-quarters of the respondents had ≥ 10 years of experience as pharmacists. This is likely due to this panel including a large number of highly specialized HCPs. A similar trend was observed in a survey conducted in Japan among other healthcare professional panels [14, 15].

Most pharmacists explained how to take IXA to their patients. However, the proportion of pharmacists with experience in using the aRMM material at the time of explanation was approximately 30%. This result is related to the fact that 187 of the 307 pharmacists who explained the contents of the aRMM material responded that they had never obtained the aRMM material. This may be because there are multiple materials containing instructions on how to take IXA. The results of Q5 (see Supplementary Table 4 in the ESM) suggested that comprehensive materials, including information on adverse events, were utilized more frequently than materials focusing on the dosing schedule of IXA. However, of those who responded that they “had obtained the aRMM material” and “explained how to take IXA to patients,” approximately 70% answered that they had used the aRMM material, suggesting that the aRMM material was being used.

Approximately 40% of respondents answered that they had obtained the aRMM material. Compared with the overall results (37.6%), a higher proportion of pharmacists working in specialized medical institutions for cancer treatment (100.0%), pharmacists specialized/licensed in cancer treatment (50.0%–71.4%), and pharmacists who fully understood the RMP for IXA (81.3%) responded that they had obtained the aRMM material. These results suggest that institutions and individuals expertized in cancer treatment obtained aRMMs more frequently. In addition, they understood the importance of explaining how to administer IXA to patients.

Globally, several challenges have been identified in the evaluation of the effectiveness of aRMMs, including difficulties in choosing feasible indicators (process and outcome indicators), burden on the healthcare system, barriers to patient and HCP access, challenges in setting thresholds for effectiveness, timing and frequency of conducting the studies, and choice of appropriate study designs and data sources [12]. Of these, the major challenges in this survey were the inability to consider outcome indicators due to feasibility and the fact that the pre-determined thresholds for effectiveness could not be set due to the limited availability of reference information.

We also identified several specific challenges in Japan regarding the effectiveness evaluation. First, measuring the effectiveness of a single piece of educational material is challenging. In Japan, the proportion of newly approved products with aRMMs is higher than in Europe and the US [16]. In addition, these materials have been used for a long time. Furthermore, multiple materials for patients/HCPs other than those developed as aRMMs commonly contain similar information. Consequently, patients and HCPs are routinely informed through numerous media sources, which makes it difficult to measure the effectiveness of a specific material alone. To overcome this, the primary endpoint of our survey was set to whether the ‘contents’ of the aRMM material are explained. Second, a unique feature of Japan is that many materials prepared as aRMMs are not intended to minimize specific risks but rather provide a comprehensive overview of the product covering various risks. Considering the risk-management cycle of medicinal products and the objective of aRMMs, defining educational materials only for specific risks as aRMMs is considered more effective. These challenges regarding the effectiveness evaluation of aRMMs warrant further discussion in light of future appropriate regulations and cases evaluated for aRMM in Japan.

Some limitations exist in interpreting the results of this survey. The first is due to selection bias. As this survey was conducted online only and the population actively participating in the survey may have different characteristics, such as higher motivation to obtain information, the analysis set may not be completely representative of the population. The second limitation is social desirability bias, in which pharmacists tend to give socially desirable/expected responses instead of reflecting on their current knowledge or behavior. This relates especially to the binary response questions, such as the questions on whether pharmacists understand how to take IXA (Q1) and whether they explain how to take IXA to patients (Q3), which may have been affected by this bias, resulting in a potential overestimation of the proportion of ‘Yes’ answers for these questions. Lastly, since this survey was self-reported and the time of obtaining the material and prescribing IXA depended on each respondent, recall bias may have occurred. Additionally, pharmacists are assumed to obtain many materials daily, which may cause confusion. However, we attempted to minimize confusion in the survey by presenting on-screen photographs of the materials during the questionnaire.

5 Conclusions

This survey confirmed that the contents of the aRMM material were explained to patients by pharmacists and that the aRMM material was utilized at the time of the explanation. These findings indicate that the aRMM material contributes to the promotion of the appropriate use of IXA. Therefore, no modification of the aRMM material is considered necessary.