Japan’s pharmaceutical market is one of the largest in the world, with figures from the Ministry of Health, Labour and Welfare (MHLW) indicating a market value of about $95 billion, including non-prescription medications.
Analysis of various experts shows that the country’s market for drugs will continue to grow, and this demand is expected to increase as the country has a rapidly aging population, and demanding new medicines for associated conditions. Over 35% of prescription drugs in Japan are imported from the USA, and this demand is expected to increase.
What is the regulatory authority in Japan?
Pharmaceuticals and Medical Devices Agency (PMDA) and The Ministry of Health, Labour, and Welfare (MHLW) are the two main regulatory agencies that review and approve the drugs in Japan.
- In the IND process, the MHLW shall be notified of the study protocol by the sponsor before and provide various requirements to be met by the sponsor when requesting medical institutions to perform clinical studies
- Once a drug completes all three phases of the clinical trial, the manufacturer must file the New Drug Application (or NDA) with the Pharmaceuticals and Medical Devices Agency (or PMDA).
- After review and evaluation by the PMDA, it provides a recommendation and forwards the application for approval to the Ministry of Health, Labour, and Welfare (or MHLW).
- MHLW issues approval or rejection on the NDAs and once a drug wins approval from MHLW, it enters into the NHI list for pricing negotiations
- The standard drug review process takes approximately 12 months, while the priority review takes nine months.
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 import and sell medical products to the Japanese market.
How can a foreign manufacturer market drugs in Japan?
Foreign Restrictive Approval
Foreign pharmaceutical manufacturers can apply directly under their name for marketing approval if they perform the studies regarding quality, efficacy, and safety required for the drugs they intend to export to Japan and perform the necessary procedures.
This is a system for a foreign company who does not have its corporation in Japan can utilize when marketing a drug in Japan
- A foreign company must assign a Japanese MAH (Designated Marketing Authorization Holder) who has all the appropriate licenses.
- Approval is granted under the condition that a designated MAH performs safety management on behalf of the foreign company.
- In addition to safety management, a designated MAH should also perform various procedures such as submission of the drug application, post-market surveillance (PMS), etc.
Foreign Manufacturer Accreditation (FMA)
An individual company that intends to manufacture drug products, quasi-drugs, cosmetics, or medical devices overseas and import them into Japan is referred to as a foreign manufacturer and must acquire a Foreign Manufacturer Accreditation (FMA) from the Ministry of Health, Labour and Welfare to market such products in Japan.
The government fee to obtain an FMA license is about 149,700 yen (document review), and the standard processing period is about 5 months.
What are the requirements and process for IND approval in Japan?
Requirements for IND approval
- Documents that give the reason why the request for the clinical study was judged to be scientifically appropriate
- Clinical study protocol
- Explanatory materials and consent form used for obtaining informed consent
- Sample of the case report form (CRF) (The sample is not required if information to be contained in the CRF is explicitly stated in the protocol.)
- Investigator’s Brochure
Process for IND approval
- Japan’s regulatory system recommends the IND Application documents to be prepared in the Common Technical Document (CTD) format.
- The applicant may schedule a pre-IND meeting (consultation with PMDA), before sending an application for Investigational New Drug (IND) to the PMDA, to ensure flawless and streamlined processing of IND approval.
- Subsequent to the application submission, PMDA evaluates the application with respect to the preclinical data, and protocols for clinical studies, etc. It may probably take 30 days for initial IND and 14 days for second and consecutive INDs.
- The queries received from PMDA should be answered by the applicant. After PMDA completes its review, the IND application will be transferred to the Institutional Review Board (IRB) for the review.
- IRB takes about 1-4 weeks of time for review.
- Once IRB provides a favorable response, the IND application will be approved after which, clinical trials can be initiated on human subjects.
What are the requirements and process for NDA approval in Japan?
Requirements for NDA
Documents are recommended to be in CTD format for Approval Application
- Documents on development or overseas use & approvals
- Documents on manufacturing methods, standards and tests, structure determination physical and chemical properties
- Stability studies document
- Pharmacological action document, ADME documents & toxicity studies
- Clinical trial studies and results
Process for NDA approval
- Application forms for approval to market drugs shall be submitted to the PMDA.
- PMDA reviews the application and schedules a face-to-face meeting with the applicant during which queries from PMDA are discussed
- GMP investigation of manufacturing sites will be carried out.
- After the face-to-face meeting, the PMDA reviewer prepares a Review Report
- If there are any major issues, PMDA organizes the Expert Discussion, which involves a discussion between the PMDA reviewer and external expert on the proposed major issue.
- After the discussions with the external expert, the PMDA reviewer will prepare a summary of the main issues and discuss with the applicant in a direct meeting that can be held 2 times.
- PMDA reviewers will submit the results of the review along with the results of GMP conformity investigation reports to the Minister of Health and Labour Welfare (MHLW).
- MHLW upon consultation with the Pharmaceutical Affairs and Food Sanitation Council will approve NDA to the applicant.
- When deliberation by the Pharmaceutical Affairs and Food Sanitation Council is completed, the Ministry of Health, Labor, and Welfare reports as being acceptable will approve new drugs after a GMP conformity investigation and through routine procedure within the MHLW.
- A drug designated as a poisonous or powerful drug or biological product appears in the government gazette.
- The approval certificate is delivered by the Evaluation and Licensing Division after the date of approval. For drugs processed by the bureau, approval certification is delivered through the PMDA.
Overview of the approval process in Japan
Orphan drug regulatory in Japan
A disease is considered to be rare if it occurs in less than 50,000 patients and Orphan drug designation can be applied for treating such rare diseases
- The medical need is especially high and 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.
- Significantly high efficacy and safety are expected from the product.
- There should be a strong rationale for the use of the product and the development plan of the product should also be valid
The generic drug approval process in Japan?
Data Required for the Approval of Generic Drugs
- An application in the common technical document (CTD) format
- The manufacturing methods, standards, and test methods, which are used for evaluations of specifications and test methods (and manufacturing methods, in some cases).
- Stability data, which is used to conduct accelerated tests.
- Absorption, distribution, metabolism, and excretion data, which are used in bioequivalence evaluations.
Biologics regulatory in Japan
- The PMDA’s Office of Biologicals provides consultations concerning clinical trials of new drugs and handles biotechnology medicines, including biosimilars
- Requirements differ depending on whether a biological product is a regenerative medicine product or not.
- The MHLW designates a product as biological after it consults with its Pharmaceutical Affairs and Food Sanitation Council
Biosimilars approval process in Japan
The PMDA’s Office of Biologicals provides consultations concerning 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 also reduce the burden if it already has information gathered for its foreign license or approval.
Requirements for approval
- The biosimilar should be fully characterized, using analytical methods.
- It should be established that the manufacturing process for the biosimilar is highly consistent.
- The dosage form and route of administration of the biosimilar product should be the same as those of the reference product.
- Long-term, real-time, real-condition stability studies should follow the ICH Q5C guideline (stability testing of biotechnological/biological products).
- A comparison of quality attributes between the biosimilar and the reference product should be conducted.
- Nonclinical studies (including pharmacokinetics, pharmacological, and toxicity studies) that can ensure the safety of administration to humans should be performed and completed prior to the initiation of clinical studies.
- Clinical studies are required whenever the data from quality characterization and nonclinical studies is insufficient to demonstrate comparability with the reference product. Clinical studies should be designed based on the data from quality characterization, nonclinical studies, and comparability studies.
- It is necessary to have had people of Japanese origin included in one of the efficacy and pharmacokinetic studies.
- If clinical data do not include any people of Japanese ethnicity, it is mandatory to show the similarity between a biosimilar candidate and the reference product according to the International Conference on Harmonization Guidelines
- Applicant fulfilling all the requirements can submit the market approval application to MHLW
- The application is then passed on to the PMDA, where it follows two necessary but different pipelines.
- The first is in the Conformity Audit Office, which verifies compliance with good clinical and laboratory practices.
- At this stage, reviewers look to visit manufacturing units
- The entire file is reviewed and meetings with the owner are scheduled in order 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, which grants or refuses the authorization for marketing the biosimilar, along with its pricing.
What is the priority review?
Drug approval reviews are normally processed in the order that the application forms are received. However, for some special considerations, the applications are review in priority. For an application shall 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
- Standpoint of efficacy
- Standpoint of safety
- Reduction of a physical and psychological burden on the patient
- When drugs are designated for priority reviews, opinions of experts on such designations are compiled by the PMDA immediately after the application and reported to the MHLW.
- Based on this report, the Evaluation and Licensing Division decides whether or not to apply for the priority review and the Evaluation and Licensing Division notify this decision to the applicant and the PMDA.
- The Evaluation and Licensing Division report this application to the next meeting of the review committee concerned with the PAFSC and obtains their approval.
- Products for priority review are given priority at each stage of the review process as much as possible.
- When a product has been designated 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 are requested to submit results of clinical studies up to late Phase II as a rule as data for estimating the clinical usefulness assessment.
- Hearings and inquiries are undertaken for the applicant as required and the designation is decided after hearing opinions of experts in the field and the results, including reasons, are notified to the applicant in writing.
- Orphan drugs are all handled as products for priority interview advice and an application is not required.
What is the Conditional Accelerated Approval System?
Drugs treating serious diseases which occur in a small number of patients and for which effective treatment methods are limited, a conditional accelerated approval system was established in which 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 of Pharmaceutical Evaluation Division
Criteria to come under this review
- Seriousness of indication
- The disease has a significant impact on lives
- The disease is progressive and irreversible
- Medical usefulness
- No existing remedies
- Greater efficacy and safety, and fewer physical and mental side effects than current treatments
- Confirmatory clinical trials are difficult to conduct or take a long time due to a limited number of patients
- Clinical trials other than confirmatory trials have shown a certain degree of efficacy and safety
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