Investigation on the accumulation of background and pregnancy outcome information on cases consulted by the Japan Drug Information Institute in Pregnancy.

Since pregnant women are excluded from clinical trials, it is essential to accumulate post-marketing information to evaluate the effects on the fetus of medication use during pregnancy. The Japan Drug Information Institute in Pregnancy (JDIIP) was established at the National Center for Child Health and Development as a Ministry of Health, Labour, and Welfare project to provide patients with information and conduct follow-up surveys. In this study, we investigated the status of the accumulation of JDIIP consultation cases to identify issues for enhancing clinical information appropriate for use during pregnancy and to examine how information should be collected and provided. In addition, the status of descriptions of Japanese package inserts, which are representative of those used by healthcare professionals as a source of information, was confirmed for medications used by JDIIP consultation cases. The characteristics of the JDIIP consultation cases information were that the contents that needed to be adjusted when evaluating the effects on the fetus of medication use during pregnancy were obtained. In addition, the follow-up rate was 83.1%. However, although the number of consultation facilities has increased, the number of consultations has not, indicating the need to further increase the number. It was found that there is limited information on epidemiological studies of clinical use in Japanese package inserts. To improve clinical information on the appropriate use of medications during pregnancy, it is necessary to accumulate more information in the future, and it is considered necessary to consider new approaches utilizing the JDIIP system.

Comparison of Addition of Indications for Antineoplastic Agents Approved in the United States and Japan from 2001 to 2020.

The indications for antineoplastic agents are limited in Japan compared with those in the United States. This may be because it takes longer to add indications and the number of additions of indications is lower in Japan than in the United States. To clarify the differences in the timing and number of additions of indications for antineoplastic agents, the agents approved from 2001 to 2020 and sold as of the end of 2020 in Japan and the United States were identified and their additions of indications were compared. Of the 81 antineoplastic agents analyzed, the proportion of agents with additional indications was 71.6 and 63.0%, and the number of additions of indications (median/average per agent) was 2/3.52 and 1/2.43, for the United States and Japan, respectively. The median date of approval for addition of indications was August 10, 2017 and July 3, 2018 for the United States and Japan (p = 0.015), indicating that the indications were added earlier in the United States. The proportion of priority review and orphan drug designation for addition of indications was lower in Japan (55.6 and 34.7%) than in the United States (80.9 and 57.8%) (p < 0.001). When indications were developed with global clinical trials or designated as orphan drugs in the United States, delays in application and approval in Japan against the United States were small (p < 0.020). New indications for antineoplastic agents should be added promptly for Japanese patients because malignancy is the leading cause of death in Japan.

Analysis of safety specifications in risk management plan at the time of drug approval and addition of clinically significant adverse reactions in the package insert post-approval in Japan.

Recently, post-marketing safety measures have been considered critical in Japan due to the globalization of drug development and the introduction of new drug approval systems. Pharmacists are expected to play an active role in ensuring the safety of drugs post-approval. Utilizing risk management plans (RMPs) to ensure safety throughout the development and post-marketing phases is becoming even more critical. In this study, we examine the relationship between the safety specifications (SSs) in RMPs at the time of drug approval and the adverse reactions (ARs) added to the clinically significant adverse reactions (CSARs) section of the package inserts (PIs) post-approval to determine whether SSs constitute useful drug information for pharmacists. The analysis included new active ingredient-containing drugs approved in Japan from FY2013 to 2019. A 2 × 2 contingency table was created and analyzed using odds ratios (ORs) and Fisher's exact test. The OR was 14.22 (95% CI: 7.85-24.77; p < .001), which indicates a strong relationship between the ARs being SSs at the time of approval and being added to the PIs as CSARs post-approval. The positive predictive value that SSs at the time of approval were added as CSARs to the PIs post-approval was 7.1%. In addition, a similar relationship was observed with the "approval in shorter-period drugs" reviewed for approval based on a limited number of clinical trials. Therefore, SSs in RMPs are important drug information for pharmacists in Japan.

Comparative Study of General Notices in Pharmacopoeias in Japan, the United States, and Europe.

Globalization of pharmaceutical supply chains has expanded and manufacturers are required to manufacture products in compliance with the pharmacopoeial standards used in all exporting countries/regions to ensure product quality. International harmonization has been facilitated by the Pharmacopoeial Discussion Group consisting of the Japanese Pharmacopoeia, the United States Pharmacopeia, and the European Pharmacopoeia. However, since the pharmacopoeias have been developed individually under the regulatory framework of each country/region, differences exist between these pharmacopoeias. When using pharmacopoeias, an understanding of common pharmacopoeial rules is essential. Clarifying the similarities and differences in the General Notices of the pharmacopoeias widely referenced worldwide is considered valuable for those already using one or two of them to access the remaining pharmacopoeias. In this study, we compared the existence of items and the contents described in the General Notices of the three pharmacopoeias to clarify the differences. Investigation of the existence of items revealed that more than 70% of the 105 items in General Notices in the three pharmacopoeias were in the entire pharmacopoeias (for Japan, including Japanese laws and notifications). Furthermore, investigating contents revealed that approximately 20% of the 105 items have some differences such as numerical values and test conditions. However, it was shown that most of the items did not have major differences. It is expected that the three pharmacopoeias will be utilized simultaneously by understanding the similarities and differences shown in this study.

Comparison of New Drug Indications Approved in the United States, Europe, and Japan from 2001 to 2020.

In Japan, there have been many requests for off-label drugs from academic societies or patient groups to the "Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs." Thus, drug indications in Japan may be limited compared to those in other countries. To clarify whether drug indications in Japan are limited, the drugs containing new active ingredients approved in Japan, the United States, and Europe from 2001 to 2020 and sold in these three regions as of the end of 2020 were identified and their indications were compared. The indications of antineoplastic agents, psycholeptics, drugs from non-Japanese companies, and drugs approved in Japan from 2011 to 2020 were limited in Japan and Europe compared to the United States. These trends were more notable among antineoplastic agents. Thirty-seven indications for 19 antineoplastic agents were approved in the United States but not in Japan, and the most common indications were urothelial carcinoma (4), hepatocellular carcinoma (3), and thyroid cancer (3). The numbers of indications and drugs with different indications in Japan and Europe were generally comparable, and no specific imbalance was observed. The same indications of antineoplastic agents should be made promptly available in Japan and Europe as in the United States, as malignancy is one of the leading causes of death.

[Survey on the Provision of Drug Information by Pharmacists to Lactating Women].

Many lactating women want to breastfeed their baby, but may be overly concerned regarding the drugs present in breast milk; this leads to unnecessary weaning. Moreover, lactating women may stop taking medications at their own discretion and may not receive adequate treatment. Therefore, pharmacists are required to provide appropriate information to lactating women. In 2020, we conducted a questionnaire survey on 1781 pharmacists with the aim of investigating the actual situation of the provision of drug information by pharmacists to lactating women. The results showed that the information source that pharmacists place more importance on is the package itself, rather than databases and books, which are considered to be appropriate sources of information on the use of medicines by lactating women. Besides, more than 90% of pharmacists answered that they would like to participate in the study session. These results indicate that it is important to set up information sources that can effectively be used at workplaces and to organize study sessions for pharmacists with the support of National Center of Child Health and Development and other bodies. By improving the environment, with the aim of further improving the level of pharmacists, pharmacists will be able to provide accurate information more appropriately.

Antihypertensive drug effects according to the pretreatment self-measured home blood pressure: the HOMED-BP study.

OBJECTIVES: To clarify whether or not the antihypertensive drug effect is proportional to the baseline pretreatment self-measured home blood pressure (HBP) in accordance with the law of initial value (Wilder's law). DESIGN: A post-hoc analysis of a multicentre clinical trial. SETTING: Outpatients across Japan with mild-to-moderate essential hypertension. PARTICIPANTS: Among 3518 randomised participants, 2423 who self-measured HBP during the pretreatment drug-free period (10-28 days after starting fixed-dose antihypertensive monotherapy) with a mean 7.0 years follow-up were eligible. MAIN OUTCOME MEASURES: We analysed individual HBP readings during pretreatment and monotherapy. RESULTS: The day-to-day HBP during both the pretreatment period and monotherapy period remains almost the same throughout each period; the results were consistent, regardless of the pretreatment HBP. Following monotherapy, the reduction in the HBP increased by 2.2 mm Hg (95% CI: 1.8 to 2.5 mm Hg) per 10 mm Hg pretreatment HBP increase, up to 11.0 mm Hg (95% CI: 9.9 to 12.0 mm Hg) among patients with an HBP ≥165 mm Hg during pretreatment. Among the 1005 patients receiving low-dose monotherapy (defined daily dose: 0.5 units), the reduction peaked at 8.9-9.1 mm Hg in those with pretreatment HBP 155-164 mm Hg and ≥165 mm Hg (p=0.88). CONCLUSIONS: According to Wilder's law, the HBP reduction due to fixed-dose monotherapy was proportional to the pretreatment HBP without any regression to the mean phenomenon. With low-dose antihypertensive drugs, however, the HBP reduction peaked in patients with a high pretreatment HBP, indicating the need for such patients to receive a sufficient amount of antihypertensive drug medication at the initial treatment. TRIAL REGISTRATION: UMIN Clinical Trial Registry (http://www.umin.ac.jp/ctr), Unique identifier: C000000137.

Development of a Logic Model for Promoting Incorporation of the Concepts of Impurity-Related ICH Guidelines into Pharmacopoeias Based on Cause and Effect Analysis.

In line with the recent globalization of the drug supply chain and promotion of the use of generic drugs worldwide, quality assurance is required for drugs globally. In particular, controlling impurities is one of the biggest areas of interest regarding pharmaceutical quality, and it is desirable that the latest scientific standards harmonized in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) are not only implemented in approval applications but also incorporated in pharmacopoeias which are public standards to ensure pharmaceutical quality more widely. However, incorporation into a pharmacopoeia takes time because careful consideration is required owing to the characteristics of a pharmacopoeia that is widely used for drugs, including those already on the market. To consider a smooth approach for the incorporation, we retrospectively examined approaches to incorporate the concepts of the ICH Q3C, Q3D, and M7 guidelines covering residual solvents, elemental impurities, and mutagenic impurities which are particularly toxic impurities into the European Pharmacopoeia, United States Pharmacopeia-National Formulary, and Japanese Pharmacopoeia, with approaches to implement these guidelines into approval processes in Europe, the U.S., and Japan. We also identified barriers and facilitators to this goal via cause and effect analysis. Moreover, we developed a logic model for the smooth incorporation of the concepts of impurity-related ICH guidelines. We expect that our proposed approach will be applied as a framework to smoothly incorporate the results of international harmonization activities for controlling impurities into each pharmacopoeia.

Blood Pressure Phenotypes Defined by Ambulatory Blood Pressure Monitoring and Carotid Artery Changes in Community-Dwelling Older Japanese Adults: The Ohasama Study.

White coat hypertension is defined as elevated blood pressure in the office, but a normal blood pressure out-of-office, whereas masked hypertension is defined as elevated blood pressure in the office, but normal out-of-office blood pressure. The objective was to investigate the associations between these blood pressure phenotypes and carotid artery changes. Conventional blood pressure, ambulatory blood pressure, and carotid ultrasonography were evaluated in 851 Ohasama residents (31.8% men; mean age 66.3 years). The blood pressure phenotypes were defined by the ordinary thresholds (140/90 mmHg for conventional blood pressure, 135/85 mmHg for daytime blood pressure) and then by the 2017 American College of Cardiology/American Heart Association (ACC/AHA) thresholds for hypertension (130/80 mmHg for both conventional and daytime blood pressure), irrespective of antihypertensive medication treatment status. Blood pressure phenotypes were linearly associated with the mean intima-media thickness of the carotid artery in ascending order for sustained normal blood pressure, white coat hypertension, masked hypertension, and sustained hypertension according to the ordinary thresholds and the 2017 ACC/AHA thresholds (both linear trends P < 0.0001) after adjustments for possible confounding factors. The odds ratios for the presence of carotid plaques showed similar linear trends with the blood pressure phenotypes according to the 2017 ACC/AHA thresholds (linear trend P < 0.0191). In conclusion, there was a close relationship between blood pressure phenotypes and carotid artery changes, suggesting that blood pressure phenotypes as defined by ambulatory blood pressure are potentially useful for risk stratification of carotid artery changes in the Japanese general population.

Comparative Study of Pharmacopoeias in Japan, Europe, and the United States: Toward the Further Convergence of International Pharmacopoeial Standards.

A pharmacopoeia's core mission is to protect public health by creating and making available public standards to help ensure the quality of drugs. In recent years, pharmacopoeias around the world have harmonized their standards in the present context of globalized drug supply chains and markets. For example, the Pharmacopoeial Discussion Group has worked to harmonize excipient monographs and general chapters. In addition, the International Meeting of World Pharmacopoeias has been held by the WHO to discuss information exchange and international collaboration, among other topics. To contribute further to the protection of public health in the globalized drug market, we conducted a comparative study of the pharmacopoeias in Japan, Europe, and the United States. We aimed to examine current differences among the Japanese Pharmacopoeia, the European Pharmacopoeia, and the United States Pharmacopeia-National Formulary and to identify areas that require further collaboration among the three pharmacopoeias. In this study, we analyzed monographs and general chapters listed in the three pharmacopoeias. We identified the features of the monographs and general chapters listed in each pharmacopoeia, as well as differences across the pharmacopoeias. Moreover, on the basis of our findings, we suggest standards that require further collaboration among the pharmacopoeias in certain preferred areas. The comparison data produced by this study are expected to be used to develop strategies for future revisions of pharmacopoeias around the world.

Regulatory convergence of medical devices: a case study using ISO and IEC standards.

INTRODUCTION: Achieving regulatory convergence is important in providing safe and effective medical devices to patients in a timely manner. The use of standards set by the International Organization for Standardization (ISO) and the International Electrotechnical Commission (IEC), may be an important tool for regulatory convergence. The International Medical Device Regulators Forum (IMDRF) published a survey and statements regarding the use of these standards in each IMDRF jurisdiction, which showed that each jurisdiction proactively uses these standards in its regulation. AREAS COVERED: This review describes the current situation by comparing the ISO and IEC standards with regulations in the European Union, the USA, and Japan on the basis of third-party certification in Japan. EXPERT COMMENTARY: Our results show that ISO and IEC standards may be important tools for regulatory convergence. However, the corresponding Technical Committees and publication editions vary in each regulation. Furthermore, there are cases in which inconsistencies between the requirements of these standards and regulation may arise. Considering this background, it is important that jurisdictions have common consensus about which Technical Committees are appropriate for the regulation of medical devices and the importance of involving standards development at an early stage to reflect regulatory opinions.