Samuel Pollard, General Manager, Vorpal Technologies - a MCRA company09.16.22
Due to high life expectancy and healthcare expenditure, the Japanese medical device and pharmaceutical sector is the world’s second-largest single country market, accounting for approximately 7% of the global market share. While this makes Japan an important part of any medtech company’s commercialization strategy, foreign manufacturers are often deterred by the language barrier, domestic footprint requirements, and need to bridge clinical data to the Japanese population. Over the last decade, Japanese regulatory authorities (PMDA and MHLW) have taken steps to harmonize efforts with the U.S. Food and Drug Administration (FDA), allowing for improved access to the Japanese market. Despite these efforts, manufacturers should be aware of unique characteristics of the Japanese regulatory process.
During the regulatory planning and consultation phase for novel products, it is important to identify and engage with key opinion leaders (KOL) to advocate for the product’s clinical need during both the regulatory and reimbursement application process. While other regulatory agencies value clinicians’ input, there is a higher degree of reliance on KOL advocacy in Japan. PMDA looks to KOLs and medical societies to understand if there is a need for novel products during the approval process as well as in determining the appropriate reimbursement category and pricing. In addition, Japanese medical societies may submit petitions to MHLW for fast-tracking through the High Needs designation for foreign-approved programs not yet progressing in Japan.
The PMDA consultation process typically begins with a free general meeting, which is intended to provide alignment on future required consultations and the product’s regulatory pathway. These additional consultation meetings may include Pre-Development Consultation to discuss in detail the required data package for a submission, Clinical Trial Necessity Consultation to discuss the need for additional clinical trial and review available clinical and/or nonclinical data, and Protocol Review Consultation to have PMDA review a clinical protocol and align on critical study design considerations.
An overseas CSR can be leveraged if it was conducted per Good Clinical Practice (GCP) and has the available documents to pass a thorough GCP audit by PMDA. If data are not available on the Asian population, a rationale must be provided to show any potential differences in race/ethnicity do not impact the study conclusions. In addition, the standard and setting of care must not impact the study conclusions.
A CER or summary of literature data can be leveraged for products deemed to have a well-known medical record and well-established safety and effectiveness evidence. PMDA will generally require proof the product is a standard treatment globally, including citations from medical society guidelines (e.g., case approved with the same U.S. indication). For novel products, it is generally difficult to leverage CER data alone as the key clinical evidence. If a CER is leveraged, it must be reconfigured to align with Japanese MHLW guidelines.
For high-risk products with limited clinical data available, a small, domestic study may be required. The requirements of this study will depend on PMDA’s views of the available data’s ability to demonstrate safety and effectiveness. If there are CSR and CER data available, then the domestic Japanese study may only be needed for confirmatory effectiveness and safety in the Japanese population (i.e., bridging study). Manufacturers should seek alignment with PMDA on the study design during the consultation and Clinical Trial Notification process. This study design and required sample size is generally dictated by the incidence of adverse events seen in global data and the product’s overall perceived risk. It’s possible to conduct a bridging study as part of post-market surveillance (PMS) requirements with MHLW/PMDA issuing a conditional approval; however, this is quite rare and requires proof the disease significantly impacts the Japanese population and confirmation conducting a clinical trial in Japan is difficult. This is most often seen with orphan indications.
Novel devices that avoid in-Japan clinical trials, in most cases, have a PMS requirement. Therefore, the overall strategy and cost should be mapped carefully to ensure the least burdensome approach for clinical data collection is undertaken.
When a new device category or technical fee is desired, differentiating the subject product from existing functional categories, a C1 or C2 application is required. C1 is an application method to create a new functional category of STM device without devising a new technical/procedure code. Alternatively, C2 application creates a new code of technical/procedure fee and can also form a new functional category of STM device. Applying for a Category C reimbursement allows manufacturers to set a product’s price much higher; however, this process is intensive with no guarantees and requires substantial support from KOL and medical societies as well as a robust dataset demonstrating the product’s benefits.
MAH is the license holder for which regulatory approval is granted. Also, distribution is not allowed in Japan without a MAH. D-MAH is similar to an MAH though its responsibility is limited to safety and quality management within Japan. A D-MAH is not the approval holder, but a Japanese local representative acting on behalf of the foreign manufacturer.
Working with a local distributor as MAH often requires the least up-front resources because the distributor will often develop and submit the regulatory submission on the manufacturer’s behalf. However, the distributor will then own the marketing authorization and have full control over the product in Japan. This can make it challenging and costly to change distributors. Setting up a local subsidiary offers manufacturers the most control; however, there can be large up-front costs with hiring the required staff to meet the in-country requirements and navigate the regulatory process. The in-country staffing requirements include three mandatory staff positions: General Production and Marketing Manager (Soseki), GVP Controller (Anseki), and QA Controller (Hinseki).
A D-MAH provider leverages their internal team to meet the in-country staffing requirements and will undertake the regulatory approval submission, obtaining other business permissions necessary for distribution. Post-market, a D-MAH provider will manage the product importation, storage, inspection, and logistics in coordination with distribution partners, maintain the quality system in accordance with QMS Ordinance within Japan, and conduct post-marketing safety surveillance and reporting in accordance with GVP Ordinance within Japan.
While Japan’s regulatory process aligns closely with overseas regulatory groups, minding the unique considerations outlined in this column will help ensure that commercialization plans are properly adapted for Japan market entry.
Sam Pollard is the general manager of Vorpal Technologies K.K.
PMDA Introduction
The Pharmaceuticals and Medical Devices Agency (PMDA) oversees Japan’s regulatory process, conducting pharmaceutical and medical device product reviews and issuing recommendations to the Ministry of Health, Labor, and Welfare (MHLW). In general, PMDA’s medical products evaluation aligns closely with international regulatory agencies. The PMDA leverages a risk-based classification system, with Class I products requiring self-registration (Todokede), Class II and Class III products with standards requiring third party certification through a Notified Body (Ninsho), and Class II - IV products without standards requiring PMDA review and MHLW approval (Shonin).During the regulatory planning and consultation phase for novel products, it is important to identify and engage with key opinion leaders (KOL) to advocate for the product’s clinical need during both the regulatory and reimbursement application process. While other regulatory agencies value clinicians’ input, there is a higher degree of reliance on KOL advocacy in Japan. PMDA looks to KOLs and medical societies to understand if there is a need for novel products during the approval process as well as in determining the appropriate reimbursement category and pricing. In addition, Japanese medical societies may submit petitions to MHLW for fast-tracking through the High Needs designation for foreign-approved programs not yet progressing in Japan.
PMDA Consultations
The first step of the regulatory approval process for a novel product is to seek input and align with PMDA on the appropriate regulatory pathway, classification, and data requirements. This is done through the PMDA Consultation process, which serves a similar role as the formal meeting process with CDER/CBER and the pre-submission process with CDRH at FDA. For novel products, these PMDA consultations are viewed as a critical part of the regulatory submission process and generally deemed to be more of a requirement as compared to FDA. For products aligning closely with predicates or with prior experience with PMDA, the consultation process can be bypassed in part or entirely. Unlike FDA meetings, PMDA consultations require applicants pay a fee for most meetings.The PMDA consultation process typically begins with a free general meeting, which is intended to provide alignment on future required consultations and the product’s regulatory pathway. These additional consultation meetings may include Pre-Development Consultation to discuss in detail the required data package for a submission, Clinical Trial Necessity Consultation to discuss the need for additional clinical trial and review available clinical and/or nonclinical data, and Protocol Review Consultation to have PMDA review a clinical protocol and align on critical study design considerations.
Clinical Data Requirements
Foreign manufacturers are often approaching PMDA after FDA clearance/approval or CE marking. Overseas data can often be leveraged to support regulatory approval, though this depends on the level and quality of available data. There are generally three approaches for meeting the clinical data requirement: Clinical Study Report (CSR) from an overseas clinical trial, Clinical Evaluation Report (CER) leveraging a summary of literature and clinical evidence, or domestic clinical trial conducted in Japan.An overseas CSR can be leveraged if it was conducted per Good Clinical Practice (GCP) and has the available documents to pass a thorough GCP audit by PMDA. If data are not available on the Asian population, a rationale must be provided to show any potential differences in race/ethnicity do not impact the study conclusions. In addition, the standard and setting of care must not impact the study conclusions.
A CER or summary of literature data can be leveraged for products deemed to have a well-known medical record and well-established safety and effectiveness evidence. PMDA will generally require proof the product is a standard treatment globally, including citations from medical society guidelines (e.g., case approved with the same U.S. indication). For novel products, it is generally difficult to leverage CER data alone as the key clinical evidence. If a CER is leveraged, it must be reconfigured to align with Japanese MHLW guidelines.
For high-risk products with limited clinical data available, a small, domestic study may be required. The requirements of this study will depend on PMDA’s views of the available data’s ability to demonstrate safety and effectiveness. If there are CSR and CER data available, then the domestic Japanese study may only be needed for confirmatory effectiveness and safety in the Japanese population (i.e., bridging study). Manufacturers should seek alignment with PMDA on the study design during the consultation and Clinical Trial Notification process. This study design and required sample size is generally dictated by the incidence of adverse events seen in global data and the product’s overall perceived risk. It’s possible to conduct a bridging study as part of post-market surveillance (PMS) requirements with MHLW/PMDA issuing a conditional approval; however, this is quite rare and requires proof the disease significantly impacts the Japanese population and confirmation conducting a clinical trial in Japan is difficult. This is most often seen with orphan indications.
Novel devices that avoid in-Japan clinical trials, in most cases, have a PMS requirement. Therefore, the overall strategy and cost should be mapped carefully to ensure the least burdensome approach for clinical data collection is undertaken.
Reimbursement Considerations
In Japan’s single-payer healthcare system, medical device reimbursement is approved by MHLW. The Japanese National Health Insurance System categorizes products into three overarching submission categories. Category A products are reimbursed as part of the specific procedure technical fee and do not receive reimbursement specific to the device. Products in this category include sutures, needles, certain imaging devices, and other general surgery devices. Category B products are Specially-Designated Treatment Materials (STM) directly reimbursed separately from technical fees based on prices set per functional category. These include established products with existing codes such as stents, artificial joints, and other well-established technologies. Receiving Category B designation following regulatory approval is a relatively straightforward process with a near guaranteed success if adopting into an existing category. It is possible to add a premium to an existing B category for an improved product, but sufficient data must be available to support the limited pricing increase.When a new device category or technical fee is desired, differentiating the subject product from existing functional categories, a C1 or C2 application is required. C1 is an application method to create a new functional category of STM device without devising a new technical/procedure code. Alternatively, C2 application creates a new code of technical/procedure fee and can also form a new functional category of STM device. Applying for a Category C reimbursement allows manufacturers to set a product’s price much higher; however, this process is intensive with no guarantees and requires substantial support from KOL and medical societies as well as a robust dataset demonstrating the product’s benefits.
In-Country Representative Requirements
In Japan, a manufacturer must have a local address and certified organization to be a Marketing Authorization Holder (MAH), or license holder, for an approved medical device. This aims to ensure there is an in-country responsible party for maintaining the quality system, potential recalls, and safety reporting. There are three options for a foreign manufacturer to meet this in-country requirement: entrust a local distributor as MAH to hold the license, invest in local infrastructure to obtain certification by setting up a local subsidiary, or appoint a qualified local D-MAH (Designated MAH) to maintain your approval in the company’s name.MAH is the license holder for which regulatory approval is granted. Also, distribution is not allowed in Japan without a MAH. D-MAH is similar to an MAH though its responsibility is limited to safety and quality management within Japan. A D-MAH is not the approval holder, but a Japanese local representative acting on behalf of the foreign manufacturer.
Working with a local distributor as MAH often requires the least up-front resources because the distributor will often develop and submit the regulatory submission on the manufacturer’s behalf. However, the distributor will then own the marketing authorization and have full control over the product in Japan. This can make it challenging and costly to change distributors. Setting up a local subsidiary offers manufacturers the most control; however, there can be large up-front costs with hiring the required staff to meet the in-country requirements and navigate the regulatory process. The in-country staffing requirements include three mandatory staff positions: General Production and Marketing Manager (Soseki), GVP Controller (Anseki), and QA Controller (Hinseki).
A D-MAH provider leverages their internal team to meet the in-country staffing requirements and will undertake the regulatory approval submission, obtaining other business permissions necessary for distribution. Post-market, a D-MAH provider will manage the product importation, storage, inspection, and logistics in coordination with distribution partners, maintain the quality system in accordance with QMS Ordinance within Japan, and conduct post-marketing safety surveillance and reporting in accordance with GVP Ordinance within Japan.
While Japan’s regulatory process aligns closely with overseas regulatory groups, minding the unique considerations outlined in this column will help ensure that commercialization plans are properly adapted for Japan market entry.
Sam Pollard is the general manager of Vorpal Technologies K.K.