Click to Read：Japanese Pharmaceutical Market & Registration Strategies – Part 1

ABSTRACT: The second article in the series focuses on strategies for success in registering products on the Japanese market, examples of non-Japanese companies successful innovative drug registration in Japan, and examples of non-Japanese companies successful generic drug registration in Japan.

Drug registration strategies for Japan

Developing a successful drug registration strategy for Japan involves tailoring regulatory approaches to align with Japan’s unique market requirements and regulatory standards, which are overseen by the Pharmaceuticals and Medical Devices Agency (PMDA) and the Ministry of Health, Labor and Welfare (MHLW).

Some of the suggested strategies that can enhance the likelihood of timely approval and market access:

1. Engaging in Early PMDA Consultations

Early Meetings: Japan offers a structured process for consultation with PMDA at various stages of development. Early engagement allows companies to understand specific regulatory requirements for their product, discuss trial designs, and clarify data expectations.

Clinical Development Plan Alignment: Obtaining feedback on clinical trial protocols before initiating studies can save time and resources by aligning with Japan’s standards and patient needs.

2. Leveraging Expedited Pathways for Innovative Drugs

SAKIGAKE Designation: Innovative drugs that target serious conditions or unmet medical needs may qualify for SAKIGAKE designation. This status offers a shorter review timeline and enhanced support from PMDA. It is ideal for therapies with high potential to impact public health, particularly those developed in Japan or with unique benefits for the Japanese population.

Priority Review: Drugs for serious conditions with significant unmet needs may be eligible for a shorter review period (around 6–9 months instead of the standard 12 months).

Conditional Early Approval: Innovative therapies with promising early-stage data (e.g., based on Phase II trials) may be conditionally approved, especially for orphan drugs or urgent medical needs. This allows faster market entry, with the condition of further post-marketing studies.

3. Localizing Clinical Development Efforts

Japanese-Specific Data: Japan often requires data from Japanese populations, especially for innovative drugs. Incorporating Japanese participants in global trials or conducting bridging studies to collect Japanese-specific data can reduce regulatory delays.

Compliance with Good Clinical Practice (GCP): Japan’s GCP standards are rigorous, and compliance is essential for trials conducted in or submitted to Japan.

4. Optimizing Data Submission and Documentation

Electronic Common Technical Document (eCTD): Japan requires submissions in eCTD format, aligned with International Council for Harmonization (ICH) guidelines. Ensuring accurate and compliant data presentation can reduce review delays.

Robust Quality and Manufacturing Data: Japanese regulators are highly focused on manufacturing quality, stability, and safety. Ensure that Good Manufacturing Practice (GMP) standards are met and provide comprehensive quality data.

5. Using Bioequivalence Data for Generic Drugs

For generic drug registration, conducting bioequivalence studies to demonstrate similar bioavailability to the innovator drug can streamline the approval process. Consider in vitro studies where applicable, as Japan may accept these for certain low-risk generics.

6. Considering Orphan Drug Status for Rare Conditions

Japan offers incentives for orphan drugs, including financial subsidies, tax breaks, and extended market exclusivity (up to 10 years). Drugs for rare diseases with limited treatment options may qualify, which can significantly reduce development costs and accelerate the approval process.

7. Preparing proactively for Post-Market Surveillance and Risk Management

Develop a Comprehensive Pharmacovigilance Plan: Japan requires post-marketing surveillance (PMS) for most drugs to monitor safety and effectiveness in real-world settings. A proactive pharmacovigilance and risk management plan aligned with PMDA’s guidelines can facilitate approval.

Adaptive Clinical Trials: For innovative therapies with conditional approval, be prepared for adaptive trials or additional post-market studies to fulfill regulatory requirements and maintain market authorization.

8. Addressing Market Access and Pricing Early

Health Technology Assessment (HTA): Japan introduced an HTA process to assess cost-effectiveness for new drugs. Engaging with PMDA early in the pricing strategy can clarify expectations and avoid pricing-related delays.

Consider Local Partnerships: Partnering with Japanese pharmaceutical companies can support market access by leveraging local knowledge, distribution channels, and regulatory expertise.

9. Monitoring Patent and Exclusivity Regulations

Data Exclusivity Periods: Japan offers 8 years of data exclusivity for new drugs. Understanding these timelines and potential patent extensions can help plan the optimal time for market entry.

Patent Protection Strategy: Addressing patent filings and legal considerations upfront helps mitigate risks associated with potential generic competition. 

10. Adapting Labeling and Packaging to Japanese Standards

Ensure that the labeling and packaging conform to Japan-specific standards, which are highly focused on clear, accurate instructions in Japanese. Labels should avoid any brand-specific terminology from other markets and include necessary information in compliance with Japan’s guidelines.

Thus, a successful drug registration strategy for Japan hinges on early engagement with PMDA, localized clinical trials, leveraging expedited approval pathways, and a proactive post-marketing plan. Addressing these factors from the outset can optimize both the approval timeline and the drug’s market positioning, making it easier to navigate Japan’s complex regulatory environment.

Examples of non-Japanese companies successful innovative drug registration in Japan

Several non-Japanese pharmaceutical companies have achieved successful registration of innovative drugs in Japan by adopting strategies tailored to Japan’s regulatory environment. Here are several examples highlighting best practices and successful approaches:

1. Localized Clinical Trials and Japanese Patient Data

Merck’s Keytruda (Pembrolizumab): Merck expanded the reach of its immunotherapy drug, Keytruda, by conducting clinical trials in Japan to gather Japanese-specific data on efficacy and safety. By including Japanese patients in global studies and conducting bridging studies, Merck ensured that PMDA had sufficient data on Keytruda’s effects within the Japanese population, ultimately leading to approval.

Learning: Demonstrating the drug's efficacy and safety in Japanese patients through local trials or bridging studies is often crucial for PMDA approval, particularly for drugs with unique mechanisms or high-risk profiles.

2. Use of SAKIGAKE Designation and Expedited Pathways

AstraZeneca’s Tagrisso (Osimertinib): AstraZeneca’s lung cancer drug, Tagrisso, received the SAKIGAKE designation, an expedited pathway for innovative drugs in Japan. This designation was granted due to Tagrisso’s potential to address unmet medical needs for patients with specific genetic mutations linked to lung cancer. The expedited status helped AstraZeneca achieve rapid approval in Japan, making it one of the first countries where Tagrisso was launched.

Learning: Applying for expedited pathways such as SAKIGAKE or Priority Review can significantly reduce time-to-market for drugs addressing urgent or unmet needs.

3. Strategic Partnerships with Local Firms for Development and Distribution

Eli Lilly and Shionogi: Eli Lilly partnered with Shionogi, a Japanese pharmaceutical company, for the development and distribution of its osteoporosis drug. By partnering with a trusted local company, Lilly gained insights into regulatory expectations, localized clinical requirements, and a streamlined path to approval. This collaboration also supported faster adoption within the market.

Learning: Collaborating with Japanese companies can improve regulatory navigation, enable shared resources for clinical trials, and ensure strong local market presence.

4. Compliance with Japan’s High Standards for Manufacturing and Quality

Roche’s Tecentriq (Atezolizumab): Roche secured PMDA approval for its immunotherapy drug Tecentriq by emphasizing compliance with Japan’s rigorous quality standards. This included investing in local manufacturing processes and ensuring all documentation adhered to Japan’s Good Manufacturing Practice (GMP) standards. Roche’s commitment to high-quality manufacturing practices helped Tecentriq quickly gain regulatory approval.

Learning: Ensuring compliance with Japanese GMP and maintaining high manufacturing standards are essential for PMDA’s approval, especially for biologics and complex therapies.

5. Post-Marketing Commitments and Pharmacovigilance

Pfizer’s Xeljanz (Tofacitinib): Pfizer’s Xeljanz, a treatment for rheumatoid arthritis, received approval in Japan after the company committed to extensive post-marketing surveillance and pharmacovigilance efforts. This included ongoing safety monitoring, as well as additional Phase IV studies to assess long-term safety and efficacy in Japanese patients. Pfizer’s robust post-marketing commitment reassured regulators and demonstrated a proactive approach to drug safety.

Learning:  Establishing a comprehensive post-marketing surveillance plan can enhance trust with PMDA and facilitate the approval process, especially for drugs with new mechanisms of action or potential safety concerns.

6. Adapting to Japan’s Health Technology Assessment and Pricing Models

Novartis’s Entresto (Sacubitril/Valsartan): Novartis worked closely with Japanese health authorities to ensure that Entresto, a heart failure treatment, was considered cost-effective under Japan’s Health Technology Assessment (HTA) guidelines. By aligning its pricing strategy to meet Japan’s HTA standards, Novartis achieved approval with an optimized reimbursement profile, supporting rapid uptake.

Learning: Adapting pricing and demonstrating cost-effectiveness through HTA assessments can help innovative therapies gain favorable reimbursement, which is key to success in the Japanese market.

These case studies illustrate that localized clinical trials, leveraging expedited pathways, partnering with local companies, prioritizing GMP compliance, robust post-market plans, and aligning with HTA requirements are key strategies for non-Japanese companies registering innovative drugs in Japan. Each approach enhances approval chances while positioning the drug for successful market entry and patient adoption.

Examples of non-Japanese companies successful generic drug registration in Japan

Here are a few examples of strategies non-Japanese companies have successfully employed to achieve generic drug registration in Japan. These strategies illustrate key factors that facilitate approval:

1. Collaborations with Japanese Partners

Mylan and Fujifilm: Mylan, a global generic drug manufacturer, collaborated with Fujifilm in Japan to enhance its market entry. The partnership leveraged Fujifilm’s regulatory expertise and established supply chain in Japan, which helped Mylan to navigate local requirements and ensure its drugs met Japanese quality standards.

Learning: Collaborating with Japanese firms allows non-Japanese companies to benefit from local knowledge, regulatory experience, and distribution networks.

2. Establishing Japanese-Specific Bioequivalence Studies

Teva Pharmaceuticals: Teva, one of the largest global generic drug companies, established its own presence in Japan and tailored bioequivalence studies specifically for Japanese regulatory requirements. They invested in local bioequivalence trials to satisfy PMDA’s standards, ensuring that their generics demonstrated comparable efficacy and safety to the brand-name drugs.

Learning: Conducting localized bioequivalence studies is often essential to meet Japan’s stringent bioavailability and efficacy requirements, even if data from other markets are available.

3. Focus on High-Quality Manufacturing and GMP Compliance

Sandoz: Sandoz, the generics division of Novartis, emphasized compliance with Japan’s Good Manufacturing Practices (GMP) and invested in advanced manufacturing processes to ensure consistent quality. By adhering to Japanese GMP standards and submitting thorough quality documentation, Sandoz gained regulatory approval for its products.

Learning: Demonstrating commitment to Japanese GMP and producing thorough manufacturing documentation are critical for meeting PMDA’s high-quality standards.

4. Utilizing Japan’s Generic Drug Incentives and Pricing System

Pfizer’s Greenstone Subsidiary: Pfizer’s generics arm, Greenstone, successfully entered the Japanese market by adapting its pricing strategy to align with Japan’s incentives for generic drugs. This included competitive pricing and demonstrating the cost-effectiveness of generics, which helped it to quickly penetrate the market.

Learning: Adapting to Japan’s pricing and reimbursement structure can make generics more attractive to healthcare providers and patients, enhancing market acceptance.

5. Strong Post-Marketing Surveillance and Pharmacovigilance

Dr. Reddy’s Laboratories: This India-based pharmaceutical company entered the Japanese market with robust pharmacovigilance and post-marketing surveillance programs. By establishing a strong post-marketing plan, Dr. Reddy’s demonstrated its commitment to ongoing safety and efficacy, which reassured both regulators and patients.

Learning: Ensuring robust post-market monitoring and adverse event reporting is essential for maintaining long-term success and compliance in Japan.

These cases show that strategic partnerships, local trial adaptation, stringent quality control, pricing alignment, and comprehensive post-marketing surveillance are pivotal factors for non-Japanese companies aiming to achieve successful generic drug registration in Japan.

Opportunities and Future Outlook for Japanese Market

Regenerative Medicine and Gene Therapy: Japan has been a pioneer in regenerative medicine regulations, especially around cell therapies and gene therapy. The “fast-track approval” system enables faster commercialization of breakthrough therapies in these fields.

Oncology and Rare Diseases: Focus areas for R&D in Japan include oncology, rare diseases, and neurological conditions. Many companies are prioritizing these fields, supported by regulatory incentives for orphan drugs and therapies for unmet medical needs.

Impact of Health Reforms: Japan continues to implement healthcare reforms aimed at controlling costs while ensuring access to quality treatments. These reforms could impact drug pricing and access, especially for innovative and high-cost therapies.

Conclusion:

Japan’s pharmaceutical market offers robust growth potential, driven by its aging population, strong healthcare infrastructure, and focus on innovation. While pricing pressures and regulatory complexities pose challenges, Japan remains an attractive market for pharmaceutical companies globally. By understanding the unique regulatory environment, cost structures, and market demands, pharmaceutical companies can find valuable opportunities for growth and expansion in Japan.

About the author

Deepak Hegde, 

Ph.D., M.F.M, is an industrial pharmacist by training. He has a been involved in development and commercialization of both innovative and generic drugs from a very early phase of development to technical transfers for commercial manufacturing sites, for the past 25 years. During his career, he has worked at Rhone Poulenc, Novartis (Sandoz), USV Ltd., WuXi AppTec, GSK & EOC Pharma. and Shenzhen Pharmacin Co. Ltd. He is currently working with as Cipla (Jiangsu) Pharmaceutical Company Ltd as General Manager & China Site Head.

Email: deepak.hegde@cipla.com