2022 年 4 巻 1 号 p. 12-19
In Japan, digitization of the package insert was stipulated in the Act on Securing Quality, Efficacy, and Safety of Products Including Pharmaceuticals and Medical Devices, amended in December 2019 and enforced on August 1, 2021. Therefore, it is possible to access the contents of the package insert that are posted on the Pharmaceuticals and Medical Devices Agency website by scanning the GS1 barcode on the outer box of the drug with a smartphone application. Additionally, the inclusion of paper package inserts in products will be abolished by the end of July 2023. The digitization of the package insert will present benefits such as convenience in utilization of package inserts, access to the latest package inserts, and saving of paper resources, despite some challenges remaining. Further linkage with other healthcare information is expected to be promoted in addition to solving these challenges.
Digital transformation (DX) has advanced in healthcare. The digitization and digitalization of medical information are at the core of DX in diagnosis and treatment. Currently, digitization and digitalization of various types of medical information are progressing in each country. The digitization of package inserts in Japan, followed by the abolishment of their insertion into the product package, is a pioneering activity ahead that of other countries. Simultaneously, it is increasingly expected that rapid progress toward the true digitalization of medical information will be achieved by linking digitized package insert information with other medical information.
The package insert in Japan is a document that is prepared by marketing authorization holders (MAHs) and describes “Matters necessary for the use and handling of pharmaceutical products, medical devices, regenerative medicine products, etc”. In the United States and Europe, the equivalents of the package insert in Japan are called Labeling [1] and Summary of Product Characteristics [2], respectively. Both the package insert in Japan and Summary of Product Characteristics are documents meant for use by healthcare professionals. Medication Guides for Patients and Patient Information Leaflets are prepared in Japan and Europe, respectively. Labeling in the United States, on the other hand, is a concept related to drug information provision, and includes Instruction for Use which is also called “Patient Labeling” as information for patients.
As the name implies, a package insert has long been provided in paper form as a document inserted into the package of the product. Currently, with progressive digitization of regulatory documents of pharmaceutical products, especially documents related to drug approval applications, package inserts have already been posted on the Pharmaceuticals and Medical Devices Agency (PMDA) website as electronic files together with other regulatory documents of pharmaceutical products. Under these circumstances, the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices (Pharmaceuticals and Medical Devices Act: PMD Act) amended in December 2019 was enforced on August 1, 2021 [3]. In the amended PMD Act, it has been stipulated that “precautions for use concerning using and handling the pharmaceuticals, medical devices and regenerative medicine products” which have been provided as described in the package insert, should be provided electronically. This marked the start of the digitization of package inserts in Japan. This paper reviews the background, purpose, content, and challenges of the digitization of this package insert, and outlines the prospects for linkage with the digitization of other pharmaceutical and healthcare information.
In the PMD Act before the amendment made in December 2019, the package insert was defined as follows: For the sake of providing information on the proper use and safety of pharmaceutical products, medical devices, and regenerative medicine products, they must have “Matters to be indicated on package inserts” described in their package inserts, containers, or capsules. Based on this stipulation, the provision of product information had been implemented as the package insert bundled with pharmaceutical products. In addition, regarding prescription pharmaceuticals, pharmaceuticals requiring guidance, and specially-controlled medical devices, “Matters to be indicated on package inserts” had been submitted to PMDA and published through the PMDA website.
Under these circumstances, the following points were raised at the meeting of the Health Sciences Council’s subcommittee for pharmaceutical and medical device regulations held on November 8, 2018 [4].
● Owing to frequent revisions of the package insert, the package insert bundled with pharmaceutical products may not be up to date.
● Whenever the same drug is delivered to a medical institution or pharmacy, many copies of its package insert are provided to one facility, leading to a waste of paper resources.
Based on these problems, the following points were considered.
● In principle, the information described in the package insert will be provided electronically.
● The provision of a package insert with the product will be abolished, and MAHs will indicate a code, such as the QR code, on the outer box of the product, with which the package insert information can be accessed.
● Sufficient period for transitional measures will be provided when revising the regulation.
Based on this examination, the digitization of the package insert was stipulated in the amendment of the PMD Act in December 2019 and enforced in August 2021. In this amendment, it has become mandatory to disclose necessary information such as on precautions for use and handling of drugs (excluding pharmaceuticals requiring guidance or OCT pharmaceuticals), medical devices (excluding medical devices, etc. provided primarily for the ordinary use of general consumers), and regenerative medicine products (hereinafter referred to as “Drugs, etc. requiring information disclosure”) by means of information communication technology, and such information has been newly defined as “Information on precautions, etc”. Namely, regarding “Drugs, etc. requiring information disclosure”, “Package insert” and the contents of the package insert called “Matters to be indicated on package inserts” have been revised to “Electronic package insert” and “Information on precautions, etc.”, respectively.
As shown in Fig. 1, because of this amendment of the PMD Act, regarding “Drugs, etc. requiring information disclosure”, MAHs should (1) post “Information on precautions, etc.” on the PMDA website, (2) indicate the code (GS1 barcode) on the outer box of the product, and (3) establish a system to provide information “Information on precautions, etc.” [5]. With these changes in regulations, the methods of providing information on the proper use and safety of pharmaceutical products have changed. In prescription pharmaceuticals, medical devices (excluding medical devices mainly intended for the ordinary use of general consumers), and regenerative medicine products, “Information on precautions, etc.” is provided electronically by publishing it on the PMDA website instead of the provision of the information by paper media (package insert). In addition, the information published on the PMDA website can be viewed by reading the code (GS1 barcode) indicated on the outer box of the product with a smartphone. As the information published on the PMDA website is always kept up to date, it is possible to access the latest “Information on precautions, etc.” at any time. The key points of this amendment are described below.
Electronic package insert system in Japan. Marketing authorization holders usually provide package inserts of their products electronically, and healthcare professionals access package inserts by scanning a GS1 barcode on the outer box of products using mobile devices (bottom). In addition to electronic provision, marketing authorization holders provide paper package inserts at the initial delivery, a revision of package inserts of their products, or upon request by a medical institution (top).
There are two actions to be taken when publishing “Information on precautions, etc.” on the PMDA website. The first is to upload an electronic file of “Information on precautions, etc.” to the PMDA website, and the second is to build a linkage between the uploaded file and the GS1 barcode information of the corresponding product. Regarding the preparation of the package insert, the Ministry of Health, Labour and Welfare (MHLW) notified instructions on April 25, 1997 [6,7,8]. In addition, submission of the package insert to the MHLW became mandatory on November 25, 2014 [9]. Since then, package inserts for prescription pharmaceuticals have been posted on the PMDA website as PDF and SGML files. Therefore, the second point must be addressed exclusively through this amendment to the PMD Act.
No period for transitional measures was set for the publication of “Information on precautions, etc.” on the PMDA website. In order to address the second point, it was necessary for MAHs to register by July 31, 2021 the information enabling linkage between the GS1 barcode and the package insert number in the safety information posting system by accessing the page for package insert information of the prescription pharmaceuticals on the PMDA website for MAHs (SKW website) [10]. In general, this series of actions requires the cooperation of the in-house administrator of the GS1 barcode, the worker who registers the information enabling the linkage on the PMDA website, and the worker who verifies that the linkage works appropriately. In Sanofi, three departments (the supply department that manages GS1 barcodes, the package insert department that makes registrations, and the manufacturing department that verifies the display of package insert information using GS1 barcodes) collaboratively completed the registration and verification of 276 codes of 92 products before the enforcement of the amended PMD Act on August 1, 2021.
Actions on products packageAs a transitional measure for “Drugs, etc. requiring information disclosure” that were manufactured and sold between the date of enforcement of the amended PMD Act (August 1, 2021) and the day when two years will have passed (until July 31, 2023), the products can include their paper package insert in which “Information on precautions, etc.” is printed [7]. In addition, it is clearly stated in another office communication that the inclusion of paper package inserts should be avoided because the purpose of the PMD Act is to promptly provide safety information etc. after the above period has passed [11]. In Sanofi, the manufacturing department has set an individual schedule on discontinuing the inclusion of paper package inserts according to the manufacturing schedule of each product and has been gradually discontinuing the inclusion of paper package inserts from September 2021 in cooperation with the marketing departments and the labeling group. Moreover, much information about the discontinuation of paper package inserts has been published in sequence on the product website.
The GS1 barcode has been adopted as the code used to access “Information on precautions, etc.” posted on the PMDA website; however, at the initial stages, the QR code system was also assumed to be a candidate. The GS1 barcode printed on each packaging unit has been used for product distribution control in the pharmaceutical industry, but there has been no such precedent in the case of a QR code. Under these circumstances, if a QR code was to be adopted, it would involve enormous cost and time to change the product design. Considering the opinions of the industry, the GS1 barcode was adopted as the code to access “Information on precautions, etc.” posted on the PMDA website.
Requirements for provision of paper package insert, and establishment of internal system and customer supportIn the amended PMD Act [3], MAHs are required to establish the system necessary to provide healthcare professionals with “Information on precautions, etc.” of a product categorized as “Drugs, etc. requiring information disclosure”. Specifically, MAHs are required to (1) provide healthcare professionals with printed “Information on precautions, etc.” of a product at the time of their first purchase of the product or the time that “Information on precautions, etc.” is amended and (2) have sufficient personnel and a standard operating procedure (SOP) to carry out the aforementioned point properly and smoothly [7].
Sanofi Japan formed a cross-functional task force on the digitization of package inserts to enforce the amended PMD Act on August 1, 2021. Since the establishment of an internal system regarding the provision of “Information on precautions, etc.” was a requirement that would have impacts on various divisions, the necessary tasks (such as SOP creation, discontinuation of inclusion of paper package inserts in each product package, medical representative training, and revision of the product website) and related departments were identified, and a sub-team was formed for each task followed by the allocation of specific work (Table 1).
| (A) System for provision of printed “information on precautions, etc.” | ||
| Timing of provision | System for provision | Responsible department |
| At first delivery | • Sales information provision activities | • Compliance division |
| • Supervising division for sales information provision activities | ||
| • Early post-marketing phase vigilance | • Pharmacovigilance department | |
| • Provision of information on additional risk minimization activities in the Risk Management Plan | ||
| At revision of “Information on precautions, etc.” | • Sales information provision activities | • Compliance division |
| • Supervising division for sales information provision activities | ||
| • Provision of information associated with safety measures | • Pharmacovigilance department | |
| Upon request by a medical institution | • Call center | • Medical information department |
| • Sales information provision activities | • Compliance division | |
| • Supervising division for sales information provision activities | ||
| (B) System for appropriate and smooth provision of “information on precautions, etc.” | ||
| Task for provision | Responsible department | Remarks |
| GS1 barcode management | Supply chain | |
| Proper display of GS1 barcode on products | Quality department | Proper preparation and management of packaging materials |
| Creation and revision of “Information on precautions, etc.” | Labeling department | Register “Information on precautions, etc.” and GS1 barcode on the SKW website |
| Procedures for addressing complaints from healthcare professionals or patients, etc. | Supervising division for sales information provision activities | Complaints about the activities of the medical representative |
| Quality department | Quality complaints through the Medical/Sales Department | |
As the understanding and cooperation of medical representatives was indispensable in terms of provision of printed “Information on precautions, etc.” to healthcare professionals in the special cases described above, several in-house trainings on the amended PMD Act were conducted for the medical representatives. In addition, an in-house call center was set up to respond to specific questions (Table 1 (A)).
Because the contents and ownership of the SOP were entrusted to MAHs, each company took a different course of action on these points. In Sanofi Japan, this requirement was addressed comprehensively considering not only the provision of “Information on precautions, etc.” to healthcare professionals, but also the need to cooperate with the distribution department and respond to problems when accessing “Information on precautions, etc.” using the GS1 barcode (Table 1 (B)).
Although this amendment of the PMD Act implies a change in the way MAHs provide customers with “Information on precautions, etc.” customer guidance was indispensable so that customers could utilize “Information on precautions, etc.” in this new way of provision. Given this was an unprecedented initiative in the pharmaceutical industry, Sanofi Japan decided to provide guidance to all delivery facilities for its products from the “Customer First” perspective. Specifically, in addition to sending a direct mail to each customer, the guidance was delivered to approximately 66,000 insurance pharmacies and hospital pharmacy departments nationwide by the “Pharmaceutical Information Lumping Delivery Service” by the Japan Pharmaceutical Association, which is a service well-known to healthcare professionals.
Access to electronic package insertThe electronic inserts published on the PMDA website can be viewed not only by directly accessing the PMDA website but also by scanning the GS1 barcode on the container of the corresponding pharmaceutical products with the smartphone application “Tembun-Navi”. Information that can be obtained using “Tembun-Navi” is provided separately for healthcare professionals and the public. “Tembun-Navi” was jointly developed by The Distribution Systems Research Institute (GS1 Japan), The Federation of Pharmaceutical Manufacturers’ Association of Japan (FPMAJ), and The Japan Federation of Medical Devices Associations (JFMDA) and has been provided free of charge since April 1, 2021.
Digitization of package inserts is expected to have benefits, such as prompt provision of the latest information on pharmaceuticals, convenience, and ecology, but some challenges are also raised (Table 2).
| Paper package insert | Electronic package insert | |
|---|---|---|
| Pros | • Neither mobile devices nor network access are required for access. | • Ability to provide up-to-date package inserts even just after the revision. |
| • Easy to access even in times of disaster or emergency. | • Paper resources are saved. | |
| • Easy to access by reading a barcode using mobile devices. | ||
| • Flexible regarding the type and quantity of information. | ||
| • Versatile in terms of linkage with other health care data. | ||
| Cons | • The package insert bundled with pharmaceutical products may not be up to date. | • Need to search the PMDA website when either the barcode or mobile device is unavailable. |
| • Paper resources are wasted. | • Need a paper package insert or downloaded data when mobile devices or network access are unavailable. | |
| • Errors may occur when scanning a barcode. |
The electronic package insert for a drug is easy to access with the corresponding GS1 barcode and “Tembun-Navi”. However, if one of them is not available, it is necessary to search the PMDA website for electronic package inserts for the required products. In addition, paper package inserts are required at a time or place where devices such as smartphones or computers cannot be used.
Promotion of digitalizationCurrently, the fact that most electronic files of electronic package inserts are PDF files indicates that the paper package insert has been digitized. In the future, it is expected that it will be easier to search or compare contents between package inserts and confirm changes at the time of update with the XML files of the electronic package inserts.
Scanning of GS1 barcodeJust after the enforcement of the amended PMD Act on August 1, 2021, some errors were reported in the correspondence between the GS1 barcode and the electronic package insert on the PMDA website, which prevented correct access to the corresponding electronic package insert. Currently, MAHs of relevant products are in the process of refurbishing these. On the other hand, as a physical problem, there have been some cases shared where (1) reading the GS1 barcode by “Tembun-Navi” is difficult because it is printed on a material other than paper depending on the packaging form and (2) identifying the GS1 barcode to access the electronic package insert is slow because two or more different types of barcodes are printed. Therefore, further improvements are warranted.
Saving paper resourcesBefore the amendment of the PMD Act, it was possible to assume that discontinuation of the inclusion of the paper package insert in the package would cause a change in the outer box size, as the paper package inserts included in each product to date also served as a cushioning material during transportation. Regarding this point, the Pharmaceutical Safety and Environmental Health Bureau of the MHLW commented that there is no legal statement about including a paper cushioning material (blank paper) in which “Information on precautions, etc.” is not described, and each MAH can take an appropriate measure [12]. However, there is also an opinion that if blank paper continues to be included in the package for the purpose of cushioning material, it goes against one of the original purposes of digitization of the package insert, “saving paper resources”. Each company should consider future measures for products facing this situation.
The package insert is a document for healthcare professionals in Japan. However, anyone can easily access electronic package inserts using “Tembun-Navi” and the GS1 barcode printed on the press-through package of medicines they take. This situation may strengthen patients’ understanding of medicines and improve treatment adherence. In addition, electronic package inserts may improve patient health literacy ultimately by improving some points such as readability, retrieval capability, and accessibility to revision history.
2. Promotion of English translationIf publication of the English translation for each electronic package insert is promoted on the PMDA website, an opportunity is presented to share the label with foreign countries as needed. Therefore, it is expected that positive impacts could be achieved during the review of drug approval applications in other countries, based on the contents of the electronic package inserts in Japan.
3. Flexibility of the amount of informationThe guideline stipulates that the paper package inserts should be within four pages in an A4-sized paper [13]. At the time of the enforcement of this amended PMD Act, the stipulation of the guideline had not been revised so that it was applicable to the electronic package inserts as well. However, it may be possible to provide a certain degree of flexibility in the amount of information owing to digitization. For rare diseases, it may be necessary to provide as much clinical data as possible at the development stage through electronic package inserts. Further discussion is needed for the flexibility of the amount of information in electronic package inserts.
4. Linkage with other healthcare informationAs mentioned, patients have access to “Information on precautions, etc.” by reading the GS1 barcode using “Tembun-Navi” on the press-through package. In consideration of this situation, there is an increasing demand for the development of an application for patients, such as an application for online medication guidance using the electronic package insert. In addition, because the GS1 barcode can be linked to various electronic information, it can be considered in the healthcare to link the electronic package insert with electronic medical records, health insurance claim data, patient prescription records, and electronic prescriptions. Furthermore, in terms of the technology used for the electronic package insert, it has been considered to apply the technology to (1) ensuring traceability of pharmaceutical products, medical safety measures, and automation of dispensing operations and (2) managing personal medication history and utilizing real-world data by linking with an individual number system named “My Number”. Thus, standardization in medical terms is expected to improve the affinity among systems for electronic healthcare information.
Linkage with PMDA medi-navi and drug safety update (DSU) 1. PMDA Medi-NaviBy registering for the free e-mail service “PMDA Medi-Navi” [14] provided by PMDA, information such as emergency safety information and revised “Information on precautions, etc.” and approval information for new drugs can be delivered quickly. In addition, with the digitization of package inserts on August 1, 2021, PMDA Medi-Navi’s optional service, My Drug Collection Creation Service, recently released a function to download package inserts for prescription pharmaceuticals. When using drugs in times of disaster or emergency, especially in rescue operation in the mountains or at sea, information related to drugs including “Information on precautions, etc.” is more important. However, with the electronic package insert, it may be difficult to access “Information on precautions, etc.” owing to impairment in the network infrastructure in such situations. With this package insert batch download function, package inserts can be downloaded on a regular basis. Therefore, the electronic package inserts can be viewed even when the medical site cannot connect to the Internet environment, such as in the event of a disaster.
2. DSUThe DSU is a summary of new precautions for using pharmaceutical products by the pharmaceutical industry, which is supervised by the Pharmaceutical Safety and Environmental Health Bureau of MHLW and edited and published by the FPMAJ. The DSU contains information on revisions of the “Precautions for Use” of prescription pharmaceuticals manufactured, sold, or imported by pharmaceutical companies participating in the Safety Measures Information Subcommittee of FPMAJ. DSU is posted on the FPMAJ website [15] and can also be accessed from the PMDA website [16]. DSU is also delivered by email to individuals who have registered with the aforementioned PMDA Medi-Navi. As DSU is an important and powerful tool for disseminating information on package insert revisions, the GS1 barcode has been printed as part of the revision information since September 2021 in accordance with the digitization of package inserts. The DSU is scheduled to be digitized after August 2023.
3. Status in other countriesIn recent years, digitalization has progressed in earnest in the fields of medicine and pharmaceuticals, and various efforts have been made worldwide. The added value of e-labeling is also recognized by the WHO and is described in the recommendations of the Extraordinary (virtual) International Conference of Drug Regulatory Authorities (ICDRA) held from September 20 to 24, 2021 [17]. In Europe, the EMA revised “the electronic product information for human medicines in the EU: key principles” at the end of January 2020 [18]. The principles of electronic product information (ePI) are expected to contribute to public health, streamline regulatory systems, align with existing legal frameworks, complement paper package leaflets, adapt to the EU multilingual environment, and interact with other digital initiatives underway at the EU and global levels.
In the United States, digital risk communication is being actively discussed, and the provision of drug information in a different manner than before is being considered.
The future direction regarding electronic package inserts is appropriate linkage with information for healthcare professionals and information for patients. Because each piece of information is digitized, it can be linked with various types of information.
As a link with healthcare information (such as electronic medical records and health insurance claim data) handled by healthcare professionals, there are already some computers for health insurance claim data in pharmacies that can confirm the contents of package inserts; however, the linkage between electronic package inserts and electronic medical records still has high hurdles. To overcome this situation, major challenges include improving the (1) penetration rate of electronic medical records [19] and compatibility and unification of systems. In contrast, the guideline for the safety management of medical information systems has been established, and version 5.1 was formulated in January 2021 [20]. In this version, the main points are support for cloud services, introduction of authentication functions, response to cyber-attacks, and the establishment of criteria for selecting external storage contractors. In addition, regarding electronic prescriptions, operational guidelines have been established, and it is stipulated that the smooth operation of electronic prescriptions and efforts for regional medical cooperation will be promoted so that the public can enjoy these benefits as soon as possible.
For patient information, the MHLW is in the process of reforming “data health”. As an outline, (1) it is possible to understand one’s own health care information through My Number, a platform with an excellent built-in user interface, and (2) information that can be viewed by the patient himself (including medical examination information, health insurance claim data, prescription information, electronic medical record information, long-term care information, etc.) will be made available to medical institutions and long-term care establishments. This will enable the public to keep track of their own healthcare information for the rest of their lives, and simultaneously, medical institutions and long-term care establishments can provide optimal medical and long-term care services based on the needs of patients and users. This does not include a concrete plan to provide patients with information on medicines. Currently, although patients can access the Medication Guides for Patients through “Tembun-Navi”, the platform was not created on the premise of linkage with other medical information for patients. A system that enables patients to properly understand the relationship between their medical information and the information on prescribed medicines needs to be built. This will serve as a basis for patients to enjoy optimal medical and long-term care services, including drug treatment, at any medical institution and/or long-term care establishments.
The authors have no conflicts of interest to declare regarding the contents of this article. No informed decision was made by anyone to sponsor this work, and no dedicated funding was granted to carry out the research. The study was conceived, executed, and written up in the course of the authors’ daily jobs.
We would like to thank all the members of the Sanofi Japan E-Labeling Task Force.
