Topics Trends in the Establishment of a New Regulatory Framework for Software as a Medical Device in Japan and the U.S.

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Ryuiku Masuda, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute (PIIPRI)

Introduction

Digital Therapeutics has been gaining attention in recent years, mainly in the U.S. since WellDoc received approval from the Food and Drug Administration (FDA) in 2010 for its "BlueStar" diabetes management application. Recently, the FDA approved AKL-T01, a game-based DTx for improving attention function in pediatric ADHD (attention deficit/hyperactivity disorder) in June ²⁰²⁰¹⁾. 1), a game-based DTx that improves the attention function of children with ADHD (attention deficit hyperactivity disorder).

In Japan, the nicotine addiction treatment application ^Cureapp2) received regulatory approval as a medical device on August 21, 2020, the first time for a treatment application, and was reportedly the first "digital medicine" in ^Japan3).

Many DTxs fall under the category of Software as a Medical Device (SaMD) under the U.S. pharmaceutical regulations. Internationally, in 2013, the International Medical Device Regulators Forum (IMDRF) defined Software as a Medical Device as software that functions as a stand-alone medical device, which is increasing and has been widely used. SaMD is already playing a role in diagnosis, treatment, and management of diseases around the world, and there are high expectations for its future. In recent years, SaMDs equipped with artificial intelligence (AI) have also emerged.

In particular, some SaMDs equipped with ML (Machine Learning)/DL (DeepLearning) are expected to continuously collect and analyze data through use and update the results to reflect them in their functions, thereby continuously changing their performance. There is a need to reconstruct the conventional pharmaceutical regulations with medical devices or drugs in mind into a system that reflects the characteristics of SaMDs, whose performance can change rapidly, or change itself can be a ^value4), and a new pharmaceutical system is being developed in line with these characteristics.

This paper discusses trends in the SaMD regulatory system, including the Digital Health Software Precertification Program (hereinafter referred to as Pre-Cert) in the United States and the Improvement Design within Approval for Timely Evaluation and Notice (hereinafter referred to as Approval Design within Approval) in Japan. The trends of the Digital Health Software Precertification Program (hereinafter referred to as Pre-Cert) in the United States and the Improvement Design within Approval for Timely Evaluation and Notice (IDATEN) in Japan are outlined. The characteristics of SaMD, "the performance of which can change rapidly, or the change itself can be a value," have the potential to create value not found in conventional drugs and medical devices, which are not updated or are updated only infrequently. Therefore, pharmaceutical companies both in Japan and overseas are incorporating digital health into their services as a total solution centered on their own pharmaceutical products, or developing digital health, including SaMD, as one of their business domains, not limited to pharmaceutical products. Or they may view SaMD as a kind of digital medicine and consider it as a kind of competitor because of its potential to deliver treatment solutions to patients to whom pharmaceuticals could not be delivered in the past, or to increase the frequency of contact with patients.

In any case, the SaMD regulatory regime is a trend that pharmaceutical companies should keep a close eye on.

Digital Health and SaMD

Just for the sake of clarity, let's review the definitions of some of these terms. The FDA defines "digital health" as a broad concept that includes mobile health, telemedicine, etc ^. SaMD is a concept that is included in digital health. SaMD is defined by the IMDRF in 2013 as stand-alone software used for medical ^purposes6). The Digital Therapeutics Alliance in the United States defines DTx as software or hardware that has evidence and regulatory ^approval7).

The terms can be generally summarized as follows.

When pharmaceutical companies consider the commercialization of solutions and services that apply digital technology as Beyond-The-Pill, it may be necessary to obtain a business license or redefine the business domain in light of the above concepts.

Application Process for Medical Devices in the U.S.

As mentioned at the beginning of this paper, there is an emphasis on restructuring the regulatory system to reflect the characteristics of SaMD, where performance can change quickly or change itself can be a value ^.) This section provides an overview of the approval process for medical devices in the United States.

The FDA classifies medical devices into Classes I-III according to the level of risk to the human body.

Medical devices that are classified as Class III in the U.S., which corresponds to highly controlled medical devices in Japan, and new ^high-risk10) medical devices must undergo clinical trials and receive PMA (Premarket Approval) approval, which is the most stringent approval process. Medical devices that are classified as Class II (equivalent to controlled medical devices in Japan) and Class I (equivalent to general medical devices in Japan) do not require PMA, but must receive 510(k) (Premarket Notification) clearance from the FDA to demonstrate Substantial Equivalence (Substantial Equivalent). Notification) clearance, which is a demonstration of Substantial Equivalence by the ^FDA11). Furthermore, for new medical devices that are not high risk and are positioned as Risk I and II, and for which there is no valid equivalent for comparison, a De Novo application can be filed, which can be reviewed in a shorter period of time compared to a PMA.

The challenge will be SaMDs that apply ML/DL, among other things: ML/DL is a system in which the artificial intelligence program itself learns, and such SaMDs could be updated in terms of performance as a medical device, data used, and intended use. The Software Precertification (Pre-Cert) Program is being tried in the U.S. to create a new system of regulation.

Pre-Cert Overview

The intent of the Pre-Cert program is to allow SaMDs to be approved more quickly if the SaMD developer, rather than the SaMD itself, has a robust culture of quality and organizational excellence, and is responsible for monitoring the SaMD's performance under real-world conditions after it is released to the market. ⁽ 2) The idea is to conduct regulatory audits of SaMDs more quickly and ^{efficiently12)}. Companies participating in the Pre-Cert pilot, which is currently under trial, will be required by the FDA to demonstrate that they are well managed and in compliance with FDA compliance, that they have a proven track record in the software product field and can be evaluated for product quality and organizational excellence, that they provide information on their post-market performance and quality management systems to the FDA The company must meet the following criteria: it must be compliant with the FDA; it must have a proven track record in the software product field and be able to demonstrate product quality and organizational excellence; and it must be willing to provide the FDA with information on its post-marketing performance and quality management system, hold discussions with the FDA, and undergo site visits. Currently, nine companies are participating in the pilot: Apple, Fitbit, Johnson & Johnson, Pear Therapeutics, Phosphorus, Roche, Samsung, Tidepool, and Verily.

This Pre-Cert incorporates new regulatory thinking for SaMD. （One such approach is the Total Product Lifecycle Approach (TPLC) (Fig. 4), in which the review of the product and the review of the development company run side by side, and the efficacy and safety of the product are monitored after launch.

PEAR THERAPEUTICS has already received approval for SOMRYST™ for the treatment of chronic insomnia as the first SaMD to be reviewed by the FDA under Pre-Cert ^.13) Pre-Cert has been criticized as having too high a hurdle for companies to meet the requirements. FDA is renewing its progress on the Pre-Cert program in September 2020, and the agency intends to expand testing of the program and move from a pilot to a trial pilot in the future. The FDA will continue to work to expand the testing of the program and move from a pilot to a transitional phase.

Overview of IDATEN

In Japan, the 2019 revision of the Pharmaceutical Affairs Law revised the law related to the development of pioneering medical devices in order to develop regulations based on the diversity and constant improvement of medical devices. In addition to the legalization of the pioneering review designation system and the conditional early approval system, a "prior notification system for confirmation of change plans of medical devices and changes according to the plans" has been introduced as a new approval system according to the characteristics of medical devices. This is an approval review system that allows continuous improvement of medical devices by confirming the change plan in the review process and allowing prompt partial change of the approved items within the planned scope. It is commonly known as IDATEN (Improvement Design within Approval for Timely Evaluation and Notice).

The previous procedures for indication expansion, etc., required that all necessary data be gathered before an application for partial change of approved items could be filed. The new system will allow for more rapid approval of medical devices that use artificial intelligence-related technologies to constantly change performance, etc., after marketing, and the addition of optional parts, etc., to improve the usability of medical devices using real world data collected after marketing. When using IDATEN for medical devices that use artificial intelligence-related technologies, the "Procedures for Preparation and Implementation of Change Plans," which describes the procedures necessary for preparing change plans, checking their validity, and confirming that the changes indicated in the change plans have been implemented, and the "Procedures for Management of Performance of Medical Devices whose Performance is Expected to Change after Market Release," which describes the procedures necessary for managing performance of medical devices whose performance is expected to change after market release. In addition, "other materials necessary for the appropriate and smooth management of artificial intelligence-related technologies" describing the procedures necessary to manage the performance of medical devices whose performance is expected to change after marketing are required to be ^attached14). The concept is based on the idea that performance, etc., will constantly change as the equipment is used, but that no decline in performance, etc., is allowed. The process must be established so that improvements in performance, etc. are constantly maintained, and the process must be evaluated as being ^{appropriate15)}.

Summary

As mentioned at the beginning of this paper, in the field of medical devices, new attempts are underway regarding pharmaceutical regulations for programs that are frequently updated, which is expected to further contribute to the improvement of the quality of medical care. In addition, outside of the SaMD framework, the number of providers and solutions for Digital Health, shown in Figure 1, will also increase dramatically in the future.

However, it goes without saying that it is the minimum responsibility of those who enter and operate in the healthcare field to ensure quality, efficacy, and safety, and to deliver beneficial solutions to consumers, regardless of whether the target is a patient or a healthy person, and regardless of whether or not the solution is regulated by pharmaceutical affairs. How to balance this element of "reliability" with frequent updates will be a major challenge for digital healthcare solutions.

In Japan, where IDATEN is now in effect, it will be necessary to reassess what is required of providers while closely monitoring the status of Pre-Cert, which is being tested in the U.S., and to consider regulations regarding artificial intelligence in medical device programs and the quality of teacher data. In addition, it will be necessary to consider regulations regarding the quality of artificial intelligence and teacher data to be included in medical device programs.

There is a movement among pharmaceutical companies to seek new business opportunities not only in the prescription drug manufacturing and sales business, but also in the so-called Beyond-The-Pill field. However, as the trend toward the implementation of digital technologies in society accelerates, it will be necessary to keep a close eye on the status of institutional arrangements for digital x health care. The digital technology is being implemented in society at an accelerating pace.

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