Biological and Pharmaceutical Bulletin
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Regular Articles
An Empirical Study of the Prescription Pattern of Drugs for Hematological Malignancies in Japan from 2010–2014
Shoyo ShibataYusuke WayamaAi TsuyukiMaiko MatsushitaKoji ChibaEri MatsukiShinichiro OkamotoTakeshi Suzuki
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2017 Volume 40 Issue 6 Pages 894-901

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Abstract

The number of elderly patients with hematologic malignancies has been steadily increasing with the aging of society. However, little research has been conducted to evaluate the prescription status of drugs for such diseases in Japan. Therefore, the aims of this study were to identify the patient population currently being prescribed drugs for hematologic malignancies in Japan and the direction of drug development. To examine the prescription pattern of drugs for the treatment of hematological malignancies in Japan from 2010–2014, we used the IMS Japan Pharmaceutical Market database and the Japanese Society of Hematology Clinical Practice Guidelines, and for drug development status, we used ClinicalTrials.gov and the University Hospital Medical Information Network Clinical Trials Registry. We found a significant upward trend in prescriptions for molecular-targeted agents, which are typically prescribed over the long term, and a significant downward trend in chemotherapeutic agents, which are usually prescribed for the short term. We also found that recent drug development in hematological malignancies has focused on molecular-targeted agents. These results suggest that drug development should be directed toward anti-tumor agents in hematological malignancies that can help maintain and improve patients’ QOL.

Japan is known as a super-aging society and currently has the highest proportion of elderly persons in the world.1) A dramatic shift from communicable to non-communicable diseases has been seen in the disease structure in Japan, with cancer as the leading cause of death, which is a trend shared among all developed countries.2)

Currently, chemotherapy, surgical treatment, and radiotherapy are the standard anticancer therapies, and most of the chemotherapeutic anticancer agents are cytotoxic. Moreover, cancer treatment has been drastically changing with advances in basic research, identifying potential molecules or proteins associated with critical pathways needed by cancer cells to survive, spread, or progress. Based on this perspective, anticancer agents that inhibit these critical signal transductions and have manageable toxicity profiles have recently been developed. For example, imatinib mesylate, a drug used for hematologic malignancies that targets the Breakpoint cluster region-Abelson (BCR-ABL) fusion proteins, has shown high efficacy in the treatment of chronic myelogenous and Philadelphia chromosome-positive leukemias. While standard anticancer therapy is cytotoxic, targeted therapies are often cytostatic, meaning that they only inhibit the proliferation of tumor cells. In this way, more and more molecularly targeted drugs are being developed for cancer therapies around the world, including in Japan.3) In addition, gene therapy47) and immunotherapy811) have been developed for hematological malignancies, suggesting that the number of the treatment options will increase in the near future.

However, currently, drastic unmet medical needs remain, and the number of novel anticancer compounds in the clinical development stage, especially in phase I clinical trials, has risen drastically,12) suggesting that the development by pharmaceutical companies, clinicians, and academic researchers of anticancer drugs with novel modes of action has been encouraged at the global level, including Japan. Indeed, previous research has clarified that Japan’s unique pricing system indirectly encourages the development of anticancer drugs in Japan.1315) It has also been reported that the Japanese pharmaceutical market will rival the global market, in which among all therapeutic areas, anticancer drugs are the most readily available.16) Furthermore, it has been reported that recent drug development in Japan has primarily targeted treatment for hematologic malignancies as opposed to solid tumors.17) Morita et al. suggested that this trend may be caused in part by the fact that orphan drug designations are more likely to be granted in association with hematologic malignancies, which enables the drugs in this area to receive faster approval by the Pharmaceutical and Medical Devices Agency (PMDA).17) Regarding the PMDA regulatory process, in 2015, Japan introduced the SAKIGAKE designation system, which includes priority consultations, prior review, priority review, and review partners, in order to promote the rapid development of innovative drugs.18) Nagai and Ozawa reported that this process might be capable of accelerating the development of novel anticancer drugs in Japan and reducing the delays seen in the U.S. and European countries.19)

All in all, in Japan, the development of anticancer drugs has been accelerated. In addition, Japan has introduced a new regulatory process to promote the rapid clinical development of anticancer drugs. Furthermore, the incidence of hematological malignancies, especially among the elderly, is increasing with the aging of society.

In this context, the primary objective of this study was to examine whether the development of drugs targeted to treat hematologic malignancies can meet both the urgent unmet medical and health economic needs in Japan using the prescription data of drugs prescribed to treat hematologic malignancies between 2010 and 2014. In devising a drug development strategy unique to Japan, it is important to consider prescription patterns from an economic perspective for the following reasons: 1) Japan is an aging society with a declining birth rate; as such, the number of the elderly patients is expected to increase in the near future; and 2) drugs for hematological malignancies are expected to exert a financial impact on patients; indeed, this fact has been recognized by both clinicians and patients.20) For example, in the United States some patients who pay more for tyrosine kinase inhibitors (TKIs) are likely to discontinue or fail to adhere to therapy.21) Although there are a lot of differences in the national health insurance system between Japan and other developed countries, both the clinical and financial aspects of this issue need to be discussed. In the present study, we use the number of prescriptions as opposed to sales data to discuss these financial aspects because it is difficult to analyze sales data in consideration of regular revisions in drug prices and approval orders for each drug. By contrast, we consider the number of prescriptions to be more suitable for analyzing financial aspects as it more accurately reflects clinical need. In addition, the number of prescriptions can be standardized using the minimum unit of each drug.

To the best of our knowledge, no previous studies have used such comprehensive and exhaustive data on prescription patterns to examine the future directions of drug development for hematologic malignancies in Japan. Therefore, this is the first study to examine the treatment of hematologic malignancies from an economic perspective. We believe that the insight obtained from this research by investigating recent prescription patterns and drug development status will help steer drug development for hematologic malignancies by clinicians, pharmaceutical companies, and academia. This study can serve as a basis to identify current unmet medical needs for future drug development based on the standard of care available and described in this study in particular for the aging population in Japan.

MATERIALS AND METHODS

Database Created for This Research

The data set used in this research was created from publically available information obtained from the IMS Japan Pharmaceutical Market database. Data on the number of prescriptions of anticancer drugs for hematologic malignancies between 2010 and 2014 in Japan were selected.

Information Collection Regarding Drugs Approved for Hematologic Malignancies

The data from the IMS database were categorized according to the first level of the Anatomical Therapeutic Chemical Classification System as follows: A stands for Alimentary tract and metabolism; B for Blood and blood-forming organs; C for Cardiovascular system; D for Dermatologicals; G for Genitourinary system and sex hormones; H for Systemic hormonal preparations, excluding sex hormones and insulin; J for Anti-infectives for systemic use; K for Transfusion; L for Antineoplastic and immunomodulating agents; M for Musculoskeletal system; N for Nervous system; R for Respiratory system; S for Sensory organs; T for Diagnostic medicine; and V for Various.

First, L drugs were selected as anticancer drugs (N=363). Next, 44 drugs listed in the Japanese Society of Hematology Clinical Practice Guidelines for the management of hematologic malignancies22) were selected as the drugs of interest, as shown in Fig. 1. Table 1 shows the list of the drugs selected for this study.

Fig. 1. The Algorithm for Hematologic Malignancy Drug Selection
Table 1. Hematologic Malignancy Drugs Enrolled into This Study
Drug name (n=44)
Arsenic trioxideIdarubicin
AzacitidineIfosfamide
BendamustineImatinib
BleomycinIrinotecan
BortezomibL-Asparaginase
BusulfanMelphalan
CarboplatinMercaptopurine
CisplatinMitoxantrone
CladribineMogamulizumab
CyclophosphamideNelarabine
CytarabineNilotinib
DacarbazinePentostatin
DasatinibProcarbazine
DaunorubicinRanimustine
DoxorubicinRituximab
EnocitabineRuxolitinib
EpirubicinSobuzoxane
EtoposideTamibarotene
FludarabineTretinoin
GemcitabineVinblastine
Gemtuzumab ozogamicinVincristine
HydroxyureaVindesine

Statistical Analysis

Univariate regression analysis was conducted to clarify prescription trends and R2 values were calculated. Values of p<0.05 were considered statistically significant. Drugs for which the number of prescriptions changed significantly between 2010 and 2014 were selected. To investigate the change in the number of prescriptions of these drugs, the ratio of the number of prescriptions in 2010 to that in 2014 was calculated.

All statistical analyses were performed using SPSS Statistics for Windows (version 22.0; IBM Corp., Armonk, NY, U.S.A.).

Information Collection Regarding the Indications for Drugs with Significant Changes in Prescriptions

The approval year and indications for the hematological malignancy drugs selected based on the results of univariate regression analysis were examined by referring to the package inserts and interview forms available on the PMDA website.23) The Japanese Society of Hematology Clinical Practice Guidelines for the management of hematologic malignancies22) provided the following indications: acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LBL), chronic myelogenous leukemia (CML), myeloproliferative neoplasms (MPN), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and myelodysplastic syndromes (MDS) for leukemia; follicular lymphoma (FL), mucosa-associated lymphoid tissue lymphoma (MALToma), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), Waldenström’s macroglobulinemia (MW), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), Burkitt’s lymphoma (BL), peripheral T-cell lymphoma (PTCL), adult T-cell leukemia/lymphoma (ATL), extranodal NK/T-cell lymphoma, nasal type (ENKL), and Hodgkin’s lymphoma (HL) for malignant lymphoma; and multiple myeloma (MM) for myeloma.

Current Drug Development Status in Anticancer Drugs in Japan

The current development status of anticancer drugs and therapies in Japan, which is represented by the number of clinical trials, was investigated by referring to ClinicalTrials.gov (https://clinicaltrials.gov/) for new drug development and the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) (http://www.umin.ac.jp/ctr/) for all ongoing clinical trials in Japan, including post-marketing surveillance studies, among others. The two sources were used to investigate the global development status and the Japanese development status, respectively. The database information on drug development was used to put the drug development trends of Japan into a global perspective. The information obtained from these databases was categorized by the following target indications: leukemia, lymphoma, or myeloma.

Objectives

The primary objective of this research was to clarify what is needed for hematologic malignancy drugs to address the urgent unmet medical and health economic needs in Japan, thereby providing direction for future drug development by pharmaceutical companies, clinicians, and academia.

RESULTS

Prescription Drug Trends for Hematologic Malignancies

For univariate regression analysis, 30 drugs with significant changes in prescription patterns were selected. Among these 30 drugs, 11 had a significantly increased number of prescriptions (Table 2). Among these 11 drugs, seven were molecularly targeted agents (azacitidine, bortezomib, dasatinib, mogamulizumab, nilotinib, rituximab, and tamibarotene), two were cytotoxic agents (hydroxyurea and mercaptopurine), and two were categorized as other (arsenic trioxide and L-asparaginase). On the other hand, among the same 30 drugs, 19 had a significantly decreased number of prescriptions (Table 2). Among these 19 drugs, 18 were cytotoxic agents (carboplatin, cisplatin, cyclophosphamide, doxorubicin, epirubicin, etoposide, fludarabine, gemcitabine, idarubicin, ifosfamide, irinotecan, melphalan, mitoxantrone, pentostatin, procarbazine, ranimustine, sobuzoxane, and vindesine) and one was a molecularly targeted agent (imatinib).

Table 2. Drugs That Showed Significant Upward, Downward, and No Statistically Significant Trends Based on Simple Linear Regression Analysis
Upward trendDownward trendNo statistically significant trend
Drug nameR2 Valuep ValueDrug nameR2 Valuep ValueDrug nameR2 Valuep Value
Arsenic trioxide0.7870.045*Carboplatin0.9530.004**Busulfan0.5440.155
Azacitidine0.9840.001**Cisplatin0.9770.001**Bendamustine0.6690.091
Bortezomib0.9710.002**Cyclophosphamide0.9550.004**Bleomycin0.0860.633
Dasatinib0.9940.0001**Doxorubicin0.880.018*Cladribine0.720.069
Hydroxyurea0.9950.0001**Epirubicin0.9050.013*Cytarabine0.6970.078
L-Asparaginase0.9590.004**Etoposide0.9940.0001**Dacarbazine0.1830.472
Mercaptopurine0.9790.001**Fludarabine0.8680.021*Daunorubicin0.0360.759
Mogamulizumab0.9190.01*Gemcitabine0.9350.007**Enocitabine0.7680.051
Nilotinib0.9830.001**Idarubicin0.8640.022*Gemtuzumab ozogamicin0.1590.506
Rituximab0.9530.004**Ifosfamide0.8150.036*Nelarabine0.570.14
Tamibarotene0.8130.037*Imatinib0.980.001**Ruxolitinib0.50.182
Irinotecan0.9870.001**Tretinoin0.5550.149
Melphalan0.890.016*Vinblastine0.3580.287
Mitoxantrone0.8660.022*Vincristine0.5540.149
Pentostatin0.8870.017*
Procarbazine0.9650.003**
Ranimustine0.9530.004**
Sobuzoxane0.9860.001**
Vindesine0.9530.004**

* p<0.05; ** p<0.01.

Actual prescription trends between 2010 and 2014 are shown in Fig. 2. The absolute values in prescriptions varied dramatically from one drug to another. However, statistically significant upward and downward trends were confirmed in several drugs. Therefore, we attempted to identify the contributing factors affecting this transition by investigating the indications for each drug approved in Japan using the information obtained from package inserts, assuming that prescription trends reflect urgent unmet medical needs.

Fig. 2. Prescription Trend of Hematologic Malignancy Drugs Enrolled in This Study between 2010 and 2014

Rate of Change Analysis of the Number of Prescription between 2010 and 2014

Fold change in the number of prescriptions in 2014 compared with that in 2010 was calculated, as shown in Fig. 3. The numbers of dasatinib and nilotinib prescriptions increased by a factor of approximately five in 2014 compared with those in 2010. Tamibarotene, bortezomib, arsenic trioxide, mercaptopurine, hydroxyurea, L-asparaginase, and rituximab prescriptions nearly doubled in 2014 compared with 2010. Notable differences were confirmed in the drugs that showed a significant upward trend. Conversely, regarding downward trends, the number of the pentostatin prescriptions decreased by about a factor of four, and the others by a factor of about two in 2014 compared with 2010, with no notable differences observed among these drugs.

Fig. 3. Ratio of the Number of Prescriptions in 2014 Compared to That in 2010

Approval Year and Indications for the Drugs Listed in Table 2

The drugs listed in Table 2 are indicated in Table 3, arranged according to the approval year regarding the first indication for hematological malignancies. Most of the drugs that showed a significant upward trend in prescriptions were approved after the year 2000. On the other hand, most of the drugs approved before the year 2000 showed a significant downward trend. Regarding indications, most of the drugs targeting leukemia showed a significant upward trend; however, these drugs were not targeted for lymphoma and myeloma. Meanwhile, two exceptions were observed—bortezomib and mogamulizumab—whose indications were only for myeloma and lymphoma (multiple myeloma and adult T-cell leukemia/lymphoma, respectively).

Table 3. Indications for the Drugs Listed in Table 2
TrendDrug nameApproval year*LeukemiaLymphomaMyelomaIndication
AMLAPLALLLBLCMLMPNCLLSLLMDSFLMALTomaMZLLPLWMMCLDLBCLBLPTCLATLENKLHLMMSolid tumor
Upward trendArsenic trioxide2004X
Azacitidine2011X
Bortezomib2010XXX
Dasatinib2009XXX
Hydroxyurea1992XX
L-Asparaginase1971XXXXXXXXXXXXXXXX
Mercaptopurine1957XXXXXX
Mogamulizumab2012XX
Nilotinib2009X
Rituximab2001XXXXXXX
Tamibarotene2005X
Downward trendCarboplatin1990XXXXXXXXXXXXX
Cisplatin2005XXXXXXXXXXXXX
Cyclophosphamide**1962XXXXXXXXXXXXXXXXXXXX
Doxorubicin1975XXXXXXXXXXXXXX
Epirubicin1989XXXXXXXXXXXXXXXXX
Etoposide1987XXXXXXXXXXXXXXXXX
Fludarabine**1999XXXXXXXXXXXXXXXXXX
Gemcitabine2013XXXXXXXXXXXXX
Idarubicin2009XX
Ifosfamide1985XXXXXXXXXXXX
Imatinib2001XXXX
Irinotecan1995XXXXXXXXXXXX
Melphalan**2001XXXXXXXXXXXXXXXXXXXXXX
Mitoxantrone1987XXXXXXXXXXXXXXXX
Pentostatin1996X
Procarbazine1978XXXXXXXXXXXXX
Ranimustine1987XX
Sobuzoxane1994XXXXXXXXXXXX
Vindesine1985XXXXXXXXXXXXXXXX

* The approval year refers to the year the drug obtained regulatory approval in Japan for hematologic malignancy as the indication. ** These drugs are indicated for certain diseases only for conditioning regimens in hematopoietic stem cell transplantation. AML: acute myeloid leukemia, APL: acute promyelocytic leukemia, ALL: acute lymphoblastic leukemia, LBL: lymphoblastic lymphoma, CML: chronic myelogenous leukemia, MPN: myeloproliferative neoplasms, CLL: chronic lymphocytic leukemia, SLL: small lymphocytic lymphoma, MDS: myelodysplastic syndromes, FL: follicular lymphoma, MALToma: mucosa-associated lymphoid tissue lymphoma, MZL: marginal zone lymphoma, LPL: lymphoplasmacytic lymphoma, MW: Waldenström’s macroglobulinemia, MCL: mantle cell lymphoma, DLBCL: diffuse large B-cell lymphoma, BL: Burkitt’s lymphoma, PTCL: peripheral T-cell lymphoma, ATL: adult T-cell leukemia/lymphoma, ENKL: extranodal NK/T-cell lymphoma, nasal type, HL: Hodgkin’s lymphoma, MM: multiple myeloma.

Current Number of Anticancer Drug Candidates in Japan

Regarding the current development status of anticancer drugs for hematologic malignancies as of this writing, out of 61 clinical trials for hematologic malignancies, 18 compounds are being developed for leukemia, 23 for lymphoma, and 14 for myeloma (Fig. 4a). Regarding ongoing clinical trials in Japan, including post-marketing surveillance studies, 236 trials are being conducted for leukemia, 215 for lymphoma, and 116 for myeloma.

Fig. 4. Current Development Status for Anticancer Drugs and Therapies in Japan

UMIN-CTR University Hospital Medical Information Network Clinical Trials Registry.

The drug profiles used in clinical trials identified on the ClinicalTrial.gov website are shown in Fig. 5. Most of the development therapies focused on molecularly targeted therapies and biologics rather than chemotherapy, suggesting that these agents, with their higher efficacy and lower toxicity, will become mainstream drugs for treating hematologic malignancies.

Fig. 5. Drug Profiles Used in Open Clinical Trials in Japan

DISCUSSION

The present study demonstrated that the majority of drugs whose indications focus on leukemia, or those approved in 2004 and subsequent years, most of which were molecularly targeted agents, showed a significant increase in prescriptions between 2010 and 2014. In Japan in 2011, there were a reported 12269 leukemia patients, 24778 malignant lymphoma patients, and 6860 multiple myeloma patients.24) Although in total, there are more malignant lymphoma and multiple myeloma patients than leukemia patients, recently developed drugs have focused on leukemia, suggesting fewer treatment options for malignant lymphoma and multiple myeloma because the number of new drugs primarily targeted for these diseases are limited. In this context, a significant increase was observed in prescriptions for mogamulizumab for adult T-cell lymphoma and bortezomib for multiple myeloma showed from 2010 to 2014, indicating that these diseases have high unmet medical needs in Japan. Therefore, the development of innovative drugs for malignant lymphoma and multiple myeloma, as well as leukemia, is strongly desired.

The number of the patients with multiple myeloma in Japan has been steadily increasing in accordance with the rapidly aging population. With this background, a significant upward trend was seen in prescriptions for multiple myeloma drugs such as bortezomib. Indeed, several new drugs for multiple myeloma have been launched in Japan since 2015, including carfilzomib, panobinostat, and pomalidomide. In addition, regarding malignant lymphoma, as shown in Fig. 4, recent clinical trials for hematological malignancies have focused on malignant lymphoma rather than leukemia. Therefore, in the near future, the current market characteristics will likely change and the number of the treatment options for malignant lymphoma and multiple myeloma will increase.

The number of dasatinib and nilotinib prescriptions increased dramatically compared with the other drugs that share an indication for CML. TKIs are effective for the treatment of CML and provide good long-term survival; this may have contributed to the increase seen in the number of TKI prescriptions.25) It is notable that of the 11 drugs that showed a significant upward trend in the number of prescriptions, seven (dasatinib, nilotinib, tamibarotene, arsenic trioxide, mercaptopurine, hydroxyurea, and azacitidine) were indicated for leukemia, two (mogamulizumab and rituximab) for lymphoma, one (L-asparaginase) for leukemia and lymphoma, and one (bortezomib) for lymphoma and myeloma. This upward trend reflected the increases observed in the incidence of hematologic malignancies such as AML, ALL, APL, CML, MDS, lymphoma, and MM in association with aging.26) The age-adjusted incidence of leukemia in Japan remained relatively stable from 1975–2011, decreasing from 5.1 to 3.8 and from 6.9 to 4.7 per 100000 men and women, respectively. However, during the same period, that of lymphoma increased from 4.5 to 10.6 and from 2.3 to 7.0, and that of MM increased from 0.9 to 2.0 and from 0.7 to 1.6 per 100000 men and women, respectively.24) In addition, a significant increase in the incidence of several subtypes of lymphoma, such as HL and non-Hodgkin’s lymphoma (NHL), has been seen in Japan compared with the U.S.27) In this context, considering that compared with leukemia, even though there are high unmet medical needs and Japanese society is rapidly aging, treatment options for lymphoma and myeloma remain limited, and thus novel drugs for these hematologic malignancies are desperately needed.

The present study also demonstrated that the development of new therapies for lymphoma and myeloma, as well as for leukemia, is being actively promoted in Japan (Fig. 4). Indeed, recent advances in the understanding of disease biology, for instance, B-cell receptor modulators, including ibrutinib, an inhibitor of Bruton’s tyrosine kinase, and idelalisib, an inhibitor of phosphatidylinositol 3-kinase for NHL,28) and immune approaches, including checkpoint blockade with anti-PD-1 antibodies and adoptive cellular therapy with chimeric antigen receptor T cells for ALL and myeloma,29) have been seen on the global level. This study confirm the same trends in Japan, and the availability of these new drugs and biological products is expected to improve in the near future, thereby providing new treatment options for existing patients, as well as advances in health care for the entire Japanese population.

All in all, based on Figs. 3–5, this study provided the perspective that drug development in Japan has been promoted in accordance with unmet medical needs and in considering of the fact that Japanese society is rapidly aging.

This study also confirmed a significant upward trend in prescriptions, specifically those for molecular-targeted agents, which are often used over the long term, and a significant downward trend in chemotherapeutic agents, which are typically prescribed for the short term. Considering that recent drug development has been focusing on molecular-targeted agents, the results of the present study suggest that drug development, even that for short-term agents, should be directed toward anti-tumor agents that can help maintain and promote patients’ QOL, although drug development is not always aligned with the patients’ needs but with pharmaceutical’s branding strategies.

This study was conducted using publically available information obtained from the PMDA to investigate the current development status of anticancer drugs, including hematological malignancy drugs, in Japan. This study also used data from the comprehensive IMS Market database to investigate the current status of the market regarding hematological malignancies. Although we identified previous information gaps in regard to current hematological malignancy drug availability and provided insights into the urgent need to develop new innovative drugs, especially for malignant lymphoma and multiple myeloma, we cannot exclude several assumptions. For example, in this study, we assumed that the number of prescriptions reflected medical need, provided that the number of the patients in this therapeutic area does not change drastically. In addition, the data used in this study regarding the number of prescriptions may include drugs indicated for both hematological malignancies and solid tumors. For example, gemcitabine obtained regulatory approval for lymphoma in 2012. In this case, the prescription data used in this study may have included the number of prescriptions for solid tumors rather than only those for hematologic malignancies.

Despite these limitations, to our knowledge, this is the first empirical study to provide an overview of treatment for hematological malignancies in Japan from an economic perspective. We hope that our findings will provide perspectives that allow a better understanding of the landscape of pharmacotherapy for hematological malignancies in Japan in the future. Although this study is focused on hematological malignancies only, it does provide a basis for future research which will address overall anti-cancer drug development in Japan.

Acknowledgments

This work was supported in part by Keio Gakuji Academic Development Funds and the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan-supported Program for the Strategic Research Foundation at Private Universities. The authors wish to thank Ryotaro Uemura, Division of Basic Education, Faculty of Pharmacy, Keio University for his comments on earlier drafts.

Conflict of Interest

Shoyo Shibata is an employee of AbbVie GK. However, being part of the company has not influenced the results and discussion in this paper.

REFERENCES
 
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