CDIMIn order to put medical devices on the market, it is necessary to obtain approval, certification or notification for each item of products to be sold, as well as permission to manufacture and sell them. This time, we will look at this approval review system and its specific contents, using mobile health products as an example.
1. Approval review system for medical devices
First, let's look at the overall picture of the approval system. The figure below shows the flow of approval review for medical devices.
① Approval application
A person who intends to obtain approval (applicant) is required to have a marketing license for the product for which they are applying (excluding manufacturing and marketing of foreign-manufactured medical devices). The applicant submits the approval application form and attached documents for the item to be applied to the Minister of Health, Labor and Welfare.
② Document review
The Pharmaceuticals and Medical Devices Agency (PMDA) will review the submitted application for approval and attached documents.
③ Reliability survey
The PMDA will conduct an on-site or written inspection to ensure that the submitted application for approval and attached documents are properly prepared.
④ Examination report
The results of reviews and investigations conducted by PMDA will be reported to the Ministry of Health, Labor and Welfare.
⑤ Consultation/recommendation
The Minister of Health, Labor and Welfare consulted the Pharmaceutical Affairs and Food Sanitation Council, Pharmaceutical Affairs Subcommittee, Medical Device In-Vitro Diagnostics Subcommittee (hereinafter referred to as the “Council”) regarding the product for which approval was requested, and after deliberation by the Council, a report was submitted to the Minister of Health, Labor and Welfare. is made. However, items consulted by the council are limited to "new medical devices" (which are clearly different from approved medical devices in terms of structure, method of use, efficacy, effect, and performance).
⑥ Examination result report
In addition to the review results by PMDA, the Ministry of Health, Labor and Welfare will compile the review process, evaluation results, etc., including deliberations by the council.
⑦ Approval
Based on the results of the above approval review, the Minister of Health, Labor and Welfare will approve the applied product. The part related to the manufacturing industry (including foreign manufacturing industry) in the figure is omitted.
2. Examples of mobile health products
Then mobile health products(Health watch), examples of "Apple's ECG application", a home electrocardiogram program, and "Apple's irregular heartbeat notification program", a home heart rate monitor programLet's take a look at the specifics of the approval review.
Since these products have become a hot topic, some of you may already be using them.
"Apple's ECG Application" is a program that creates, records, stores, transfers, and displays single-channel ECGs similar to Lead 1 ECGs. The operation is to create a single-channel electrocardiogram using the Apple Watch's electrical sensor, and the installed program (algorithm) performs signal processing, feature extraction, and rhythm classification (sinus rhythm or atrial fibrillation). It is displayed on Apple Watch as data.
This is the program medical device explained in the last time (a program that contributes to the diagnosis of diseases and has the purpose as a medical device and may affect the life and health of the user, and it is not possible to install it etc.) It can be said that it gives a function as a medical device to a general-purpose computer etc.).
"Apple's Irregular Heartbeat Notification Program," which analyzes pulse rate data, detects and notifies the user of irregular heartbeats suggestive of atrial fibrillation, is also a programmed medical device.
These two programmed medical devices are categorized as "disease diagnostic programs", classified as "controlled medical devices" as Class II (relatively low risk to the human body), and "Apple's ECG application" is classified as "household precautions". "Electrometer Program" and "Apple's Irregular Heartbeat Notification Program" are commonly referred to as "Home Heart Rate Monitor Programs".
3. Approval review for medical devices as an example of mobile health products
Now, let's look at the cases of "Apple's electrocardiogram application" and "Apple's irregular heartbeat notification program" according to the flow of medical device approval review.
The information in the explanation is based on the administrative documents disclosed by the Ministry of Health, Labor and Welfare and the corporate documents disclosed by the Pharmaceuticals Agency based on the information disclosure request.[1]。
(1) Application for approval
The applicant is "Apple Inc." (hereafter "Apple"), but because it is a foreign corporation (U.S.), it does not have a manufacturing and sales business in Japan. I am applying by This is a system that allows foreign manufacturers to directly obtain approval for medical devices to be exported to Japan. At the time of application, a Japanese medical device marketing authorization holder (“designated foreign-manufactured medical device marketing authorization holder ( Appointed marketing authorization holder)”) must be appointed.
Next, I would like to talk about the approval application form and attached documents. This application for approval includes the classification, name, purpose or effect of use, shape, structure and principle, raw materials, performance and safety standards, method of use, storage method and shelf life, manufacturing method, manufacturing site of the item to be manufactured and sold. is listed.
On the other hand, the attached materials indicate the application classification (new medical device, improved medical device (no approval criteria, clinical), improved medical device (no approval criteria, no clinical), generic medical device) (no approval criteria/no clinical trials), generic medical devices (with approval criteria/no clinical trials)).
"Apple's ECG App" and "Apple's Irregular Heartbeat Notification Program" are advanced medical devices (no approval criteria, clinical), and all documents are required.
B. Materials related to development history and usage status in foreign countries
B. Materials related to verification of design and development
C. Materials related to compatibility with basic requirements standards
2. Materials related to risk management
E. Materials related to the manufacturing method
F. Materials related to clinical trial results
G Materials related to post-marketing plans
H. Documents related to the items listed in package inserts, etc.
② Document review
PMDA will review the submitted application for approval and attached documents.
Approval review of medical devices is to check whether the properties, quality and performance of the applied medical devices are appropriate. )), specific classification (7)[2]Medical devices are required to comply with the standards ("Article 42 standards"). In addition, it is said that types for which approval criteria are established can be approved only by confirming their suitability.[3]。
There are no Article 42 criteria or acceptance criteria for disease diagnostic programs, so in principle, compliance with basic requirements is examined. These basic requirements stipulate general requirements for medical devices, design and manufacturing requirements for medical devices, etc.[4]. In particular, for programmed medical devices, the following items are stipulated as "Considerations for medical devices that use programs."
・Medical devices that use programs (including medical device programs or medical devices that are recording media that record them; the same shall apply hereinafter) shall be designed to ensure reproducibility, reliability and performance of the system in light of the purpose of use. must be designed. Adequate measures shall be taken to eliminate or reduce, as far as is reasonably practicable, the risks that may arise from any failure of the system.
・Regarding medical devices using programs, the quality and performance should be verified in consideration of the life cycle of development based on the latest technology, risk management, and confirmation and verification methods for proper operation of the medical device. must be in place[5]。
Whether or not these basic requirements are met is checked during the approval review. In addition to non-clinical, clinical, and biostatistics reviewers with specialized knowledge in medicine, dentistry, pharmacy, veterinary medicine, science, biostatistics, etc., the review is conducted by multiple people. Based on the approval application form and attached documents, the review side asks questions and problems as inquiries, and confirms points as confirmation items. During the review process, expert discussions may be held with external experts.
Let's take a look at the approval application forms and attachments submitted for "Apple's ECG application" and "Apple's irregular heartbeat notification program" and the content of the approval review. In addition, since these products fall under risk category II as improved medical devices, approval or non-approval is determined by document review, and deliberations at the council of the Ministry of Health, Labor and Welfare are not conducted.
First of all, regarding the approval application form and attached documents to be reviewed, we obtained the following approval application form and attached documents by requesting information disclosure from the Ministry of Health, Labor and Welfare and PMDA (A4 size 98 pages and 99 pages respectively ( including application form)). The content corresponds to 1 to 1 shown above, but the main types of personal information are architecture, modules, performance/safety test methods, application verification, algorithms, clinical trials (part of data), and other personal information. The part was undisclosed (blacked out).
In addition, we have received the following inquiries and confirmations from PMDA during the document review and their responses.
A total of 65 pages of "Apple's electrocardiogram application" were disclosed, but a total of 180 pages of contents such as SOFTWARE DESIGN SOECIFICATION, Wireframes, Clinical Trial Protocol Appendix, platform verification report, etc. were not disclosed.
"Apple's Irregular Heartbeat Notification Program" has disclosed a total of 69 pages of inquiry responses, but the main A total of 133 pages of content were not disclosed.
Next, let's take a look at the content of the review. Approximately 90 inquiries (including confirmation items), etc., were submitted over six times using Apple's ECG application. Although some of the inquiries overlapped in terms of content and areas, these inquiries were divided as follows (total exceeds 100% due to overlap).
About 30% related to package inserts and information provision, about 20% related to clinical trials, about 10% related to performance such as algorithms, and related to application forms (name, shape, structure/principle, designated marketing authorization holder). about 30%, and others (similar products, personal information protection, cyber security, etc.) about 20%.
On the other hand, "Apple's Irregular Heartbeat Notification Program" received about 90 inquiries in a total of seven times. About 20% are related to package inserts and information provision, about 20% are about clinical trials, about 10% are about performance such as algorithms, and about application forms (name, shape, structure/principle, designated marketing authorization holder). about 20%, and others (similar products, personal information protection, cyber security, etc.) about 40%.
Below are some specific examples of inquiries and responses regarding clinical trials. Regarding clinical trials, the main issue was the clinical positioning of the product. In the approval review of these products, expert discussions were held with external experts during the review process.
As a result of these exchanges of inquiries and responses, all responses from the applicant were accepted, and it was decided that the results of the examination could be approved, and the Minister of Health, Labor and Welfare approved four months after the application.
This time, we have explained the approval review system for medical devices using mobile health products as an example. Approval reviews involve detailed checks on the properties, quality, and performance of medical devices.
Next time, we will explain the approval review case of mobile health products for medical devices.
[1] "Apple's electrocardiogram application" and "Apple's irregular heartbeat notification program" foreign-manufactured medical device marketing approval application, attachments, and approval review results are administrative documents disclosed by the Ministry of Health, Labor and Welfare. (Pharmaceutical Proceedings No. 0415 No. 42 issued by the Ministry of Health, Labor and Welfare), and the response to inquiries regarding medical device approval applications is based on the decision to disclose corporate documents disclosed by the Pharmaceuticals Agency (PMD Notification No. 0404009).
[2] Artificial blood vessel standard, medical adhesive standard, medical X-ray device standard, ventilator alarm standard, vision correction contact lens standard, biological raw material standard, non-visual correction contact lens standard, remanufactured single use medical device standards
[3] Contact lens standard, intraocular lens standard, percutaneous coronary angioplasty catheter standard, hemodialyzer, hemodiafiltrator and hemofilter standard, central venous catheter standard, wound dressing/protective material standard, accelerator 43 standards such as system standards
[4] General requirements (design, risk management, performance and function, shelf life/lifetime, transport/storage, effectiveness), design and manufacturing requirements for medical devices (chemical properties, prevention of microbial contamination, etc.) Consideration for usage environment, consideration for measurement and diagnostic functions, consideration for medical devices using programs, consideration for mechanical hazards, consideration for medical devices that supply energy and substances, medical care intended for use by general users equipment), information provision to users, performance evaluation/clinical studies
[5] Compliance with JIS T 2304 is considered as confirmation of compliance with Article 12, Paragraph 2.
Author: Tokuya Okanouchi
All rights reserved for this column.
Tokuya Okanouchi (CDI Medical Co., Ltd.)Managing Consultant）
Completed Graduate School of Pharmaceutical Sciences, Shizuoka Prefectural University, Completed Law School at Toin University of Yokohama, and completed Business School at the University of Massachusetts Lowell. Doctor (Pharmacy), Doctor of Law, MBA (Master of Business Administration)
After working at the Ministry of Health, Labor and Welfare, the National Hospital Organization, the Pharmaceuticals and Medical Devices Agency, the National Institute of Health Sciences, the Ministry of the Environment, the Ministry of Justice, and Kanagawa Prefecture.