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Biologics and Biosimilar Regulation and Registration in Japan (PMDA)

  • With the exception of the United States, Japan's biosimilar business, with a market value of $140 million, accounted for just 5% of the global market for biologics.

  • Japan's biosimilar business appears to be headed for faster growth despite a slow start. The patient co-pay dynamic, financial incentives, and business model of the nation will be crucial to success.

This article outlines the Biologics and Biosimilars regulation and registration in Japan (PMDA)

Biologics  Biosimilar Regulation Registration Japan (PMDA)

Regulatory Authority in Japan

The regulation and registration of biologics and biosimilars in Japan is overseen by the Pharmaceuticals and Medical Devices Agency (PMDA), which is the regulatory authority responsible for evaluating and approving these products.

In Japan, biologics are complex therapeutic products derived from living organisms or cells. They include a wide range of products such as monoclonal antibodies, vaccines, gene therapies, and other cellular and gene-based products. Biosimilars are biological products that are highly similar to an already approved reference biologic product, with no clinically meaningful differences in terms of safety, efficacy, and quality.

Biosimilars are patentable as long as the biologic drug complies with the Patent Act's broad conditions in Japan. As with the patent linkage system in the Drug Price Competition and Patent Term Restoration Act (commonly known as the Hatch-Waxman Act) and the patent dance system in the Biologics Price Competition and Innovation Act of 2009 (the "BPCIA") in the United States, Japan has not yet established a statutory system that coordinates the relationship between market approval for generic medicines or biosimilar medicines and the patent status of their branded originals.

Clinical trial Requirements

  1. Clinical Trial Design: Clinical trials for biosimilars in Japan typically follow the principles of the International Conference on Harmonisation (ICH) guidelines, including those for pharmacokinetics, pharmacodynamics, safety, and efficacy. The design of the trial should aim to establish the biosimilar's similarity to the reference product.

  2. Comparator: The reference product used in the clinical trial should be an approved biologic that has been authorized for use in Japan. The biosimilar is compared to the reference product in terms of safety and efficacy.

  3. Equivalence and Non-Inferiority Trials: Clinical trials for biosimilars often use equivalence or non-inferiority study designs. These designs aim to demonstrate that the biosimilar is not clinically inferior to the reference product by a predefined margin.

  4. Pharmacokinetic (PK) and Pharmacodynamic (PD) Studies: PK and PD studies are conducted to assess the similarity between the biosimilar and the reference product in terms of how the drug is absorbed, distributed, metabolized, and excreted, as well as its effects on the body.

  5. Immunogenicity Assessment: Immunogenicity studies are important to evaluate the potential for immunogenic responses to the biosimilar, including the development of anti-drug antibodies. These studies help ensure that the biosimilar does not trigger adverse immune reactions.

  6. Clinical Efficacy and Safety Trials: Clinical efficacy and safety trials are conducted to compare the biosimilar's performance to the reference product in specific patient populations and indications. The trials aim to show equivalent therapeutic outcomes and comparable safety profiles.

Required Documents

  • Application Dossier

  • Investigator's Brochure (IB): A comprehensive document that provides essential information about the biologic, including its composition, pharmacology, non-clinical data, and any known or potential risks.

  • Quality Data: Detailed information about the biologic's manufacturing process, including raw materials, production methods, and quality control procedures. This includes documentation of Good Manufacturing Practices (GMP) compliance.

  • Non-Clinical Data: Data from non-clinical studies conducted to assess the safety, pharmacokinetics, pharmacodynamics, and toxicology of the biologic. This data helps establish a foundation for the safety of the product.

  • Clinical Trial Protocols and Reports: Detailed protocols and reports from clinical trials conducted to evaluate the safety and efficacy of the biologic. This includes information about study design, patient populations, endpoints, statistical analysis, and results.

  • Pharmacokinetics and Pharmacodynamics (PK/PD) Data: Data demonstrating how the biologic is absorbed, distributed, metabolized, and excreted in the body, as well as its effects on the body's processes.

  • Immunogenicity Data: Information about the potential for the biologic to induce an immune response in patients, including the development of anti-drug antibodies.

  • Safety Data: Comprehensive safety data, including adverse event reports and analysis of potential risks associated with the use of the biologic.

  • Comparative Quality Data: For biosimilars, data demonstrating the similarity between the biosimilar and the reference product in terms of quality attributes, such as structure, purity, and potency.

  • Risk Management Plan (RMP): A plan outlining how the risks associated with the biologic will be monitored and managed once it is on the market. This includes post-marketing surveillance and reporting of adverse events.

  • Labeling and Package Insert: The proposed labeling, package insert, and prescribing information for the biologic, including dosing instructions, indications, contraindications, warnings, and precautions.

  • Summary of Product Characteristics (SmPC): A detailed document that provides healthcare professionals with comprehensive information about the biologic's use, dosage, administration, and potential risks.

  • Environmental Risk Assessment (ERA): For certain biologics, an ERA may be required to assess potential environmental impacts associated with their use and disposal.

The regulatory pathway for biosimilars in Japan involves a stepwise approach

  1. Reference Product Selection: The applicant selects a reference biologic product that has been approved and marketed in Japan. The reference product serves as the basis for demonstrating similarity in terms of quality, safety, and efficacy.

  2. Comparability Studies: The applicant conducts a series of studies to demonstrate that the biosimilar is highly similar to the reference product in terms of quality attributes, such as structure, purity, and potency. These studies include analytical, non-clinical, and clinical assessments.

  3. Clinical Trials: Clinical trials are conducted to assess the safety and efficacy of the biosimilar in comparison to the reference product. These trials are designed to detect any potential differences between the biosimilar and the reference product.

  4. Extrapolation: If the biosimilar demonstrates similarity to the reference product in terms of quality, safety, and efficacy, extrapolation may be applied. Extrapolation allows the biosimilar to be approved for additional indications without conducting separate clinical trials for each indication, provided that scientific justification supports this approach.

  5. Regulatory Approval: Based on the data generated from analytical, non-clinical, and clinical studies, the applicant submits a marketing authorization application to the PMDA. The PMDA evaluates the data and determines whether the biosimilar can be approved for use in Japan.

  6. Fees: MHLW fee for biologicals review is 618.65 USD and PMDA fee 989.15 USD.

  7. Timelines for biologicals approval vary between 30 days to two months.

Post Marketing Surveillance

Pharmaceutical post-marketing safety control methods must be established by manufacturers, and they must adhere to the standards outlined by the MHLW. These methods include gathering and reviewing information about quality, efficacy, and safety, as well as other information required for their appropriate use. Biosimilar pharmaceuticals are free from this criterion, including post-marketing safety control research, if their efficacy and safety are guaranteed by the original biologics drugs.

Manufacturers are advised to investigate the safety profiles of biosimilar medications, according to an MHLW recommendation. The recommendation also calls for manufacturers to plan for risks that could not be adequately assessed by the equivalence/homogeneity evaluation during the development stage, develop an appropriate post-marketing surveillance plan based on those risks, and submit it to the authority when applying for approval. Additionally, the recommendation stipulates that, following the approval of the biosimilars, the authority shall receive the outcomes of such a post-marketing surveillance plan by the relevant deadline.

  1. Pharmacovigilance System: Biologic manufacturers are required to establish and maintain a pharmacovigilance system to continuously monitor and assess the safety profile of their products. Adverse events and other safety-related information are collected, analyzed, and reported to the PMDA.

  2. Adverse Event Reporting: Healthcare professionals and patients are encouraged to report any adverse events, unexpected side effects, or quality-related issues associated with biologics and biosimilars to the manufacturer or to the PMDA through the Adverse Drug Reaction Reporting System.

  3. Risk Management Plans (RMPs): Manufacturers may be required to develop risk management plans as part of the approval process. These plans outline how potential risks associated with the product will be monitored and managed during its commercial use.

  4. Regular Safety Updates: Manufacturers are often required to provide regular safety updates to the PMDA, detailing any new safety information, adverse events, or changes in the risk-benefit profile of their products.



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