The Japanese drug approval process is less complex and easy compared to some other country regulators beyond the language barriers. The consultations provided by the PMDA experts help in understanding the requirements and precise stepwise process for the drug approval.
Japan’s pharmaceutical market is one of the largest in the world. The market value, including non-prescription medications, is about $95 billion as per the figures from from the Ministry of Health, Labour and Welfare (MHLW).
Various experts analysis shows that the country’s market for drugs will continue to grow. Due to a rapidly aging population and requirement of new medicines for associated conditions, the demand is expected to increase.
Over 35% of prescription drugs in Japan are imported from the USA, and this demand is expected to increase further.
Regulatory authority for drug approval in Japan
The two key regulatory bodies that review and approve pharmaceutical drugs in Japan are
- Pharmaceuticals and Medical Devices Agency (PMDA) and
- Ministry of Health, Labour, and Welfare (MHLW)
Who can apply for drug approval?
Only a local entity qualified as a Marketing Authorization Holder (MAH) or a Designated Marketing Authorization Holder (DMAH) may register, import, and sell medical products in the Japanese market.
How can a foreign manufacturer market drugs in Japan?
In order to gain approval and market their pharmaceutical products, Foreign manufacturers need to fulfil the following criteria:
Foreign Restrictive Approval
- It is possible for the foreign pharmaceutical manufacturers to apply directly under their name for market approval.
- Foreign manufacturers need to perform studies to demonstrate the quality, efficacy, and safety of the drugs they intend to export to Japan, in addition to other necessary procedures.
Foreign Manufacturer Accreditation (FMA)
- An individual overseas company that intends to manufacture drug products, quasi-drugs, cosmetics, or medical devices and import into Japan is referred to as foreign manufacturers.
- Foreign manufacturers need to obtain a Foreign Manufacturer Accreditation (FMA) from the Ministry of Health, Labour, and Welfare to gain approval and market their products in Japan.
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The regulatory process for Investigational New Drug (IND) approval in Japan
- Applicant should prepare the Investigational New Drug (IND) application documents as per the Common Technical Document (CTD) format.
- The applicant may schedule a pre-IND consultation with PMDA, before sending an IND application. Such consultation ensures flawless and streamlined processing of IND applications.
- After submission of application, the Pharmaceuticals and Medical Devices Agency (PMDA) evaluates the application with respect to the preclinical data, protocols for clinical studies etc.
- It may probably take 30 days for the initial Investigational New Drug (IND), but 14 days for second and consecutive INDs.
- The applicant needs to answer the queries received from Pharmaceuticals and Medical Devices Agency (PMDA) in a timely manner.
- Once Pharmaceuticals and Medical Devices Agency (PMDA) completes its review, the Institutional Review Board (IRB) gets to review the Investigational New Drug (IND) application.
- Institutional Review Board (IRB) takes about 1- 4 weeks of time for review.
- A favorable response from the Institutional Review Board (IRB) leads to the approval of Investigational New Drug Application. Subsequently, the sponsor can initiate clinical trials on human subjects.
Investigational New Drug (IND) approval process flow
New Drug Application (NDA) regulatory process in Japan
- Applicant submits the New Drug Application forms for the market approval to Pharmaceuticals and Medical Devices Agency (PMDA).
- The PMDA reviews the application, and if required, schedules a face-to-face meeting with the applicant.
- During the meeting, the applicant gets to discuss and ask queries from Pharmaceuticals and Medical Devices Agency (PMDA).
- After the face-to-face meeting, the Pharmaceuticals and Medical Devices Agency (PMDA) reviewer prepares a review report.
- If there are any major issues, the Pharmaceuticals and Medical Devices Agency (PMDA) organizes the Expert Discussion. This involves a discussion between the Pharmaceuticals and Medical Devices Agency (PMDA) reviewer and external expert on the proposed major issue.
- The reviewers submit the results of the review along with the results of GMP conformity investigation reports to the Ministry of Health and Labor Welfare (MHLW).
- Upon consultation with the Pharmaceutical Affairs and Food Sanitation Council (PAFSC), the Ministry of Health and Labor Welfare (MHLW) approves the New Drug Application (NDA).
- The Evaluation and Licensing Division is responsible to deliver the approval certificate after the date of approval.
- For the drugs processed by the bureau, the Pharmaceuticals and Medical Devices Agency (PMDA) delivers the approval certification.
Regulatory process flow for New Drug Application (NDA) approval
Complete overview of approval process in Japan
Regulatory for orphan drugs in Japan
Japan considers a disease as a rare disease if it occurs in less than 50,000 patients. Drug manufacturers can apply for orphan drug designation for treating such rare diseases.
Criteria for orphan drug designation approval
- The medical need is especially high.
- The intended use is for severe diseases such as intractable diseases.
- In addition, the following conditions must be met
- No other drug or medical treatment is available for the disease of concern.
- Product exhibits significantly high efficacy and safety.
- A strong rationale exists for the use of the product.
- Development plan of the product is a valid plan.
Generic drug approval process in Japan
The Pharmaceuticals and Medical Devices Agency (PMDA) is the authority for generic drug applications review in Japan. This review includes the assessment of bioequivalence, which is equivalence to the original drugs. Bioequivalence assessment helps in confirming the quality, efficacy, and safety, on the basis of documentation submitted by the generic drug applicants.
In Japan, the drug product can apply as a generic drug, if
- It contains an API (Active Pharmaceutical Ingredient).
- API has a different hydrate form or crystalline form from the original drug.
- APhas basically the same chemical structure as the original drug.
Biologics & Biosimilars regulatory in Japan
- The PMDA’s office of biologicals provides consultations concerning clinical trials of new drugs and handles biotechnology medicines, including biosimilars.
- Requirements for biologics differ depending on whether a biological product is a regenerative medicine product or not.
- The Ministry of Health and Labor Welfare (MHLW) designates a product as a biological drug after it consults with its Pharmaceutical Affairs and Food Sanitation Council (PAFSC).
The PMDA’s Office of Biologicals provides consultations on clinical trials of new drugs and handles biotechnology medicines, including biosimilars.
Biosimilar drugs are considered as those that are “equivalent and homogenous to the reference biological product in terms of efficacy, quality, and safety.”
The approval of biosimilar products in Japan tends to reduce the amount of new information required and the approval timeline.
The applicant can reduce the burden if it already has information gathered for its foreign license or approval.
Biosimilars approval process in Japan
- Applicants fulfilling all the requirements can submit the market approval application to the MHLW, which passes it further to the PMDA.
- At this stage, reviewers may look to visit manufacturing units.
- During the review process, reviewers assess the entire file and may schedule meetings with the owner. As a result, applicant gets a chance to discuss all aspects of the approval of this product.
- Once this stage of the review ends, the PMDA produces a detailed report, which is sent to the Pharmaceutical and Food Safety Bureau of the MHLW.
- Upon review of this report, the MHLW grants or refuses the authorization for marketing the biosimilar, along with its pricing.
Various fast track approval processes for drugs in Japan
Drug approval reviews are normally processed in the order of application forms received. However, for some special considerations, the applications are reviewed in priority.
An application should fall under one of the following criteria to get priority review.
- The seriousness of indicated diseases:
- Diseases with important effects on patient’s survival (fatal diseases)
- Progressive and irreversible diseases with marked effects on daily life
- Overall assessment of therapeutic usefulness
- There is no existing method of treatment, prophylaxis, or diagnosis.
- Therapeutic usefulness with respect to existing treatment.
Products under priority review get priority at every stage of the review process as much as possible.
Priority review process
- When drugs are designated for priority review, expert opinions on such designations are compiled by the PMDA immediately after the application and are reported to the MHLW.
- Based on this report, the Evaluation and Licensing Division decides whether or not to apply for the priority review.
- The Evaluation and Licensing Division will notify its decision to the applicant and the PMDA.
- When a product has been selected for priority review at the development stage, it is possible to obtain priority interview advice on indications and other items concerning the designated product.
- Applicants should submit results of clinical studies up to late Phase II for estimating the clinical usefulness.
- All orphan drugs are handled for priority interview advice and a separate application is not required.
Conditional accelerated approval system
A conditional accelerated approval system is applicable for those drugs which are used to treat serious diseases and/or occur in a small number of patients and effective treatment methods are limited.
In the conditional accelerated approval system, the results of confirmatory clinical trials are not required, but the conduct of necessary post-marketing surveys, etc. is required as a condition for approval by the Pharmaceutical Evaluation Division.
Criteria for applications to come under the conditional accelerated approval system
- Considering the seriousness of the indication
- The disease has a significant impact on public lives.
- The disease is progressive and irreversible.
- Considering medical usefulness
- No existing remedies are available.
- Greater efficacy and safety, with fewer physical and mental side effects, compared with the current treatments.
- Confirmatory clinical trials are difficult to conduct or take a long time due to the limited number of patients available for conducting clinical trials.
- Clinical trials other than confirmatory trials have shown a certain degree of efficacy and safety.
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