Drug Approval Process in Japan

Japan is one of the world's biggest pharmaceutical markets, making the development and approval of new drugs in Japan a top priority for pharmaceutical companies. Understanding the specific requirements and processes for drug submissions and approvals in Japan is crucial for global teams collaborating with Japanese teams and colleagues.

This article aims to present Japan-specific submission requirements and the review/approval process of the Japanese health authority, PMDA (Pharmaceuticals and Medical Devices Agency), with a focus on requirements that may differ from global processes.

The drug approval process in Japan is less complex and easy when compared to some other countries beyond the language barriers. In addition to regulatory considerations, the PMDA offers sponsors consultation to assist them in understanding the prerequisites and the detailed procedure for drug approval. As a result of this positive change, many manufacturers choose to register and sell their medicines in Japan.

Japan New Drug Application (J-NDA)

The J-NDA (Japan New Drug Application) submission and review/approval processes share similarities with those of the FDA (Food and Drug Administration) and EMA (European Medicines Agency), but there are important differences to note. One key difference is the mandatory submission of key results for the Japanese population when Japan participates in global or regional studies. This requirement demands substantial programming support.

Like the FDA and EMA, programming involvement is essential for creating the CSR (Clinical Study Report) and CTD (Common Technical Document) for a Japan submission. However, pooling adverse events from multiple studies may require additional programming support due to the inclusion of different indications, necessitating familiarity with PMDA's requirements.

The review time after filing a J-NDA is comparable to that of the US and EU, with a standard filing taking 12 months and "Orphan Drug Designation" taking 9 months. Throughout the review process, two significant periods of PMDA questions occur. The first round of questions arises after the Mendan meeting (a face-to-face meeting with PMDA approximately 2-3 months after filing), while the second round occurs after the GCP (Good Clinical Practice) compliance check by PMDA inspectors but before the Expert Review meeting. 

PMDA may travel to sites in other countries for GCP inspections. Questions received during the first period are generally of a general nature, while those in the second period require substantial programming involvement, necessitating careful planning.

Submission and Review/Approval Process

How can a foreign manufacturer market drugs in Japan?

To gain market approval for drugs and medical devices, foreign manufacturers need to fulfill the following criteria:

Foreign Manufacturer Accreditation (FMA)

• A foreign manufacturer is an individual overseas company that intends to manufacture drugs, quasi-drugs, cosmetics, or medical devices and import them into Japan.
• Foreign manufacturers need to obtain a Foreign Manufacturer Accreditation (FMA) from the Ministry of Health, Labour, and Welfare to market their products in Japan.

Foreign Restrictive Approval

• For foreign pharmaceutical manufacturers, It is possible to apply for market approval directly under their name.
• Along with other necessary procedures, foreign manufacturers need to perform clinical studies to demonstrate the quality, efficacy, and safety of the drugs they intend to export to Japan.
• Fee for New Accreditation for Foreign Manufacturers

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• PMDA is the agency that reviews submissions of applications for drug approval, foreign manufacturer accreditation (FMA), drug master file (DMF) registration, etc
• PMDA (Pharmaceuticals and Medical Devices Agency) is a Japanese regulatory agency, working together with the Ministry of Health, Labour, and Welfare.
• Its obligation is to protect public health by assuring the safety, efficacy, and quality of pharmaceuticals and medical devices.

Approval application for Marketing a Drug

When marketing a drug, it is necessary to obtain approval for each product by receiving examinations on both its efficacy and safety.

• Only a MAH license holder can submit an approval application for a product.
• To obtain product approval, the manufacturer in Japan needs to be licensed. For a foreign manufacturer, a Foreign Manufacturer Accredited Certificate (FMA) is required.
• The application is sent to the PMDA and further examination is mainly conducted by this agency.

Application Fee for New Drug

Description	Total Fee (Yen)
Drug containing the new ingredient, drug for a new route of administration, drug with a new combination, biotechnology based existing drug (excluding an orphan drug)	31,068,900
Drug containing the new ingredient, a drug for a new route of administration, drug with a new combination, biotechnology-based existing drug (orphan drug)	23,847,800
Drug with a new indication, drug with a new dosage form, drug for new dosage, and drug with similar formulation (excluding an orphan drug)	14,230,600
Drug with a new indication, drug with a new dosage form, drug for new dosage, and drug with similar formulation (orphan drug)	10,957,300

Required Documents

Required Documents	Contents	Modules
Documents     on      origin      or course of discovery and usage	Status      of     development and comparison of package insert with similar drug.	Module-1
Documents on manufacturing method and test methods	Structure Determination and    physical    -    chemical property	Module-3
Documents on stability	Long term stability test, accelerated test	Module-3
Documents on pharmacologic actions	Test supporting efficacy Module 4 /safety pharmacology	Module-4
Documents on clinical test results	Phase 1, phase 2, phase 3	Module-5

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The Investigational New Drug (IND) approval process in Japan

• The Japanese regulatory authority follows the Common Technical Document (CTD) drug application format and hence the applicant should prepare the Investigational New Drug (IND) application and documents as per the CTD format.
• Before making an application, the applicant may schedule a pre-IND consultation with PMDA as such consultations help to ensure a flawless and streamlined IND application process.
• Initial IND consultations may take up to 30 days, but subsequent consultations may only require 14 days.
• After the applicant applies, the PMDA evaluates the preclinical data, protocols for clinical studies and other necessary documents.
• The applicant must respond promptly to the PMDA’s questions during the evaluation..
• Once the PMDA completes its review, then the next step is to get approval from the Institutional Review Board (IRB). The IRB takes about 1- 4 weeks for review and approval.
• The sponsor can begin clinical trials on human subjects if the IRB approves the IND application following a favorable response.

Investigational New Drug (IND) approval process flow

New Drug Application (NDA) approval process in Japan

• Applicant submits the New Drug Application (NDA) forms to the PMDA for market approval.
• The PMDA then reviews the application, and if they feel necessary, may schedule a face-to-face meeting with the applicant.
• During the meeting, the applicant needs to discuss and answer the queries from PMDA, and after the face-to-face meeting, the PMDA reviewer prepares a review report.
• If the PMDA finds any critical issues during the review, it organizes an Expert Discussion. It involves a discussion between the PMDA reviewer and an external expert on the proposed critical issue.
• After review, the experts submit the results along with GMP conformity investigation reports to the Ministry of Health and Labor Welfare (MHLW).
• The MHLW, upon consultation with the Pharmaceutical Affairs and Food Sanitation Council (PAFSC), the Ministry of Health and Labor Welfare (MHLW) may approve the New Drug Application (NDA).
• After the approval, the MHLW’s Evaluation and Licensing Division issues the approval certificate.
• The PMDA delivers the approval certification for the drugs reviewed by the bureau.

Regulatory process flow for New Drug Application (NDA) approval

Complete overview of the approval process in Japan

Registration of Pharmaceuticals

• An “Applicant” is required to submit an “Application for Accreditation” (Form No. 18 in the PAL Enforcement that is addressed to the Regulations) and Minister, “Application for Accreditation Examination” [Form No.16- (2)]
• Documents to Be Attached to the Accreditation Application:

1. A medical certificate from a physician that indicates whether or not an “Applicant” has mental disorders or is addicted to narcotics, cannabis, opium, or stimulant drugs.
2. A curriculum vitae of the person who is responsible for the manufacturing establishment
3. When radiopharmaceuticals are included a document on the type of the radiopharmaceuticals and outlines of factors for handling such radiopharmaceuticals

DMF Application

• MF registrant: A manufacturer of drug substances, etc.
• Documents required: Application form, supporting data
• When to submit: As needed
• Benefits of using MFs

1. Protection of manufacturer's intellectual properties
2. The smooth operation of the regulatory marketing approval process

•  MF system is not mandatory
• PMDA only inspects whether the application is in the correct format or not.

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