Introduction to Market Growth

According to the news (23年度国内医療用薬市場　最高額の11兆3707億円に　製品売上１位はキイトルーダ　オプジーボに買控えか | ニュース | ミクスOnline (mixonline.jp)) released by MixOnline on 22/05/2024, IQVIA announced that Japan’s domestic pharmaceutical market reached an unprecedented high of 11.3707 trillion yen for the fiscal year 2023 (April 2023 – March 2024), marking a 3.7% increase from the previous year. Significant expansions in the oncology, diabetes, chronic kidney disease, influenza, and COVID-19 antiviral treatment markets drove this growth.

Top Performing Products

Keytruda (Pembrolizumab) reclaimed the top sales position, surpassing Opdivo (Nivolumab), which experienced a 4.2% revenue decline in Q1 2024 due to a 15% price cut in April.

Oncology Market Dominance

The oncology market grew by 9.8% to nearly 2 trillion yen, representing 17% of the domestic market. Keytruda led with a 22.5% increase to 164.8 billion yen. Opdivo grew by 3.5% to 164.5 billion yen but fell to second place due to market recalculation impacts. Imfinzi (Durvalumab) posted a 116% growth, reaching 120.7 billion yen, following new cancer indications.

Significant Growth in the Following Therapeutic Areas

• Diabetes Treatments: Up 7.1% to 723.7 billion yen, with a solid performance from Forxiga (Dapagliflozin) and Jardiance (Empagliflozin).
• Immunosuppressants increased 8.6% to 621.4 billion yen, led by Dupixent (Dupilumab).
• Antivirals: Grew by 48.6% to 530.6 billion yen, driven by Lagevrio (Molnupiravir) and other antivirals.

Corporate Performance

Chugai Pharmaceutical and AstraZeneca topped the sales charts, each exceeding 500 billion yen. Chugai led for the third consecutive year with 539.8 billion yen in sales, while AstraZeneca’s sales surged by 12.6% to 513.1 billion yen. MSD climbed to third place with a 30.2% increase to 497.2 billion yen, thanks to Keytruda and Lagevrio.

Conclusion

Japan’s pharmaceutical market demonstrated robust growth in FY2023, driven by advancements in oncology and other therapeutic areas. New drug developments and broader indications for existing treatments are anticipated to continue expanding the market.

Introduction to Regulatory Changes

According to the news (【中医協】薬価収載「年7回」に　　従来は年4回、25年1月から開始 | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)) released by NIKKAN YAKUGYO as of 15/May/2024, the Japanese Ministry of Health, Labour and Welfare announced at the Central Social Insurance Medical Council (Chuikyo) general assembly a significant change in the pharmaceutical regulatory landscape. In response to altering the approval timings for manufacturing and marketing of drugs, the ministry has decided to increase the frequency of Chuikyo’s drug price listing reviews from four to seven times a year, starting January 2025.

Historical Review and Approval Process

Historically, the Pharmaceutical Affairs and Food Sanitation Council’s (PAFSC) two divisions have convened bi-monthly over four sessions per year – January & February, April & May, July & August, and October & November –, with March, June, September, and December serving as the “approval months.” Typically, products reviewed in, for instance, the January & February sessions, would be collectively approved in March. Subsequently, according to the “60-day & 90-day rules,” these products would undergo price listing discussions by Chuikyo, aligning with the quarterly approval schedule.

New Operational Procedures from 2025

With the new operational changes set for January 2025, reviews will follow each bi-monthly session in January, February, April, May, July, or August within three weeks respectively, with an additional combined session for approvals in October and November. Thus, the Health Insurance Bureau anticipates seven drug price listings per year. The Bureau aims to expedite regulatory approval and drug price listing processes to enable quicker patient access to new drugs.

Committee Perspectives on Faster Drug Access

Committee member Matsumoto Masato from the Federation of Health Insurance Societies emphasized the benefits of faster access to new drugs for patients and argued for increased frequency in special price recalculations. He highlighted the importance of timing over frequency in listing new drugs to quickly mitigate the financial impact on patients and health insurance. The Health Insurance Bureau acknowledged these points as subjects for future consideration.

Introduction

According to the news (ALS薬、国内初の治験GL策定へ　　和泉研究班、最新手法で開発促進・ラグ解消 | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)) released by NIKKAN YAKUGYO as of 10/05/2024, a research team led by Professor Yuinobu Izumi at Tokushima University is set to develop Japan’s first clinical trial guidelines for Amyotrophic Lateral Sclerosis (ALS) treatments this spring. The aim is to integrate the latest methodologies to expedite new drug development and reduce drug lag and loss, with a completion target for the fiscal year 2026.

Urgent Need for New ALS Treatments

Japan has around 10,000 ALS patients, and existing treatments offer limited efficacy and only modest benefits in slowing disease progression. New treatments like Biogen’s Tofersen and Amylyx Pharmaceuticals’ AMX0035 have shown promise internationally, raising calls for their early approval in Japan.

Addressing Clinical Trial Challenges

Japan lacks standardized clinical trial guidelines, hindering efficient and timely drug evaluations. This new project will create guidelines inspired by Western models but adapted to Japanese clinical evidence. Recommendations will include innovative trial designs, such as platform and adaptive trials, and biomarkers for better patient selection and efficacy assessments.

Conclusion

By developing these guidelines, the team seeks to align Japanese ALS research with international standards, facilitating the rapid development of effective treatments for ALS patients.

According to the news (小児用薬の計画策定推奨で通知　　4月1日から適用、厚労省医薬局 | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)) released by NIKKAN YAKUGYO on March 29, 2024, the Ministry of Health, Labour and Welfare in Japan issued on March 29 an updated notification effective from April 1, asking pharmaceutical companies to provide a pediatric drug development plan before submitting J-NDA (new drug application) for adult use. The notification encourages using clinical data from adult and non-Japanese pediatrics, real-world data, and modeling & simulation to set appropriate pediatric dosages and formulations. PMDA will establish a “Pediatric Drug Development Plan Consultation Service“ and recommends using such a system. In response to a question on whether it is “mandatory” to formulate a development plan for pediatric drugs when developing drugs for adults, PMDA stated that it is desirable to formulate a development plan for pediatric drugs. Still, it is not mandatory, clarifying that it relies on a corporate decision. This policy aims to accelerate pediatric drug development in Japan.  

According to the article (Different Development Strategies Affecting Japan’s Drug lag between Japan-Based and Foreign-Based Companies | Therapeutic Innovation & Regulatory Science (springer.com)) recently published by Dr. Uyama (Associate Executive Director at PMDA), understanding regional drug development strategies is key in the competitive realm of pharmaceuticals, particularly for those looking to navigate the Japanese market. A recent study comparing strategies over a decade (2012–2021) reveals stark differences in how Japanese and foreign companies approach drug development and licensing, shedding light on the “drug lag” issue. 

Key Insights: 

• Development Approaches: Japanese firms predominantly utilize an “only-Japan” strategy for 51.1% of products, focusing on domestic markets. Foreign firms, conversely, often adopt “Multi-Regional Clinical Trials (MRCT)” strategies for 54.9% of their products, indicating a more global outlook. 
• Licensing and Drug Lag: Japanese companies show a preference for original products with minimal drug lag when there’s “no approval in the US and EU” (59.1%). However, the figure for “license-in” products with a drug lag of ≥5 years is 52.5%. This trend is not seen in foreign companies’ products. 
• Global Collaboration: The data suggests a pressing need for Japanese firms to engage in global partnerships, especially with emerging foreign companies, to reduce drug lag by considering earlier licensing and adopting global development strategies. 

 These findings highlight the importance of strategic planning and partnerships in Japan for international business development professionals in the pharmaceutical sector. Embracing a global approach, including engaging in MRCTs and fostering early-stage collaborations, could be key to minimizing drug lag and maximizing market presence. 

The ICH S1B(R1) guideline, published on the ICH official website on August 4, 2022, gives an opportunity for the exemption of long-term rat carcinogenicity studies based on the results of the Weight of Evidence (WoE) evaluation. PMDA issued related guidelines on March 10, 2023, incorporating revisions to ICH S1B(R1) and establishing a consultation framework to discuss potential exemptions based on these guidelines. Critical points of implementation in Japan are as follows:

• A new category of PMDA consultation, “S1B(R1) consultation,” is now available to discuss the possibility of exempting a rat carcinogenicity study based on WoE.
• Pre-consultation meetings are mandatory for applicants wishing to implement this consultation.
• Documents submitted for consultation should include detailed background information, non-clinical and clinical result summaries, WoE approach summaries, and relevant attachments like references and investigator brochures.

Source: 000265889.pdf (pmda.go.jp)

According to the news “「日本人データなしの薬事申請可」、厚労省・通知へ　　海外で主要な臨床試験完了など全条件該当なら | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)” released by NIKKAN YAKUGYO on 5/Mar/2024, the Japanese Ministry of Health, Labour and Welfare has proposed a new policy allowing drug applications without Japanese clinical trial data under specific conditions, aiming to enhance drug discovery and ensure a stable drug supply. This policy applies when the pivotal clinical trials conducted overseas have been completed, and it is hard to conduct clinical trials in Japan due to the too small patient population in Japan. Moreover, the overall drug’s potential benefits for Japanese patients must be deemed to outweigh the risks. Such NDA filing under this new policy may follow a conditional approval system, requiring post-approval assessment of efficacy and safety in the Japanese population. This approach is designed to seek expedited treatment access while addressing the nuances of drug development and approval in Japan, especially for diseases with urgent or unmet medical needs.

According to the news “”BS同等性試験、民族差ない場合は日本人データ不要に　　厚労省、Q＆A改訂 | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)“”  released by NIKKAN YAKUGYO on 25/1/2024, the Ministry of Health, Labour and Welfare announced a significant update to the regulatory framework for biosimilar approval. The “Questions and Answers (Q&A) on Guidelines for Ensuring the Quality, Safety and Efficacy of Biosimilar (BS)” in an administrative communication dated January 25, 2024, now clarifies that clinical trials enrolling Japanese subjects to verify the equivalence of BS with its predecessor are no longer mandatory if ethnic factors are deemed unlikely to influence the study outcomes. Consequently, clinical trial data from non-Japanese subjects can be used for regulatory approval. This change from the previous requirement, which mandated at least one of the clinical trials to verify the bioequivalence of pharmacokinetics and efficacy must enroll Japanese subjects, streamlines the development and approval process for biosimilars for international biotech and pharmaceutical companies aiming for the Japanese market.

According to the news “オーファン指定制度の要件明確化　　厚労省、優先審査は従前基準のみ | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)” released by NIKKAN YAKUGYO on 16/01/2024, the Ministry of Health, Labour and Welfare in Japan issued a notice on 16/01/2024, informing about the revision of the orphan disease designation system. This revision clarifies that applications that calculate a patient population of less than 50,000 by adding prefixes such as “serious” or qualifiers without clear medical or pharmaceutical reasons, known as “sliced applications,” are not accepted. However, this revision specifies that certain exceptions, particularly for areas with high unmet needs but lacking therapeutic development, do not fall under the “sliced application” category. The exceptions are based on appropriate medical and pharmaceutical grounds, such as age groups (including children), treatment regimens, and the necessity for medication. The notice also refined the criteria for medical needs. It states that a condition satisfies the requirements if multiple treatment or prevention options are clinically necessary and the use of currently approved drugs alone are insufficient. Examples include cases where a new mechanism of action is expected to be effective based on non-clinical trial results or when administration becomes possible for patients who have difficulty using existing drugs.

According to the news “国際共同治験前の日本人P1は原則不要　　医薬局、通知・事務連絡で明確化 | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)” released by NIKKAN YAKUGYO on 26/12/2023, the Ministry of Health, Labour and Welfare in Japan announced on 25/12/2023 that, in principle, there is no need to conduct additional Japanese Phase 1 clinical trials before multi-regional clinical trials (MRCTs) except when deemed necessary. In addition to issuing new administrative communications, the announcement also involves revising and removing previous notices and communications that stipulated the need for Japanese Phase 1 trials before MRCTs. The separate attachment of the new notice dated 25/12/2023, titled “Basic Principles for Conducting Phase 1 Studies in Japanese before Initiating MRCTs Including Japan for Drugs in Which Early Clinical Development is Preceding Outside Japan,” states that Phase 1 trials do not need to be conducted separately for each race, ethnicity, country, or region. It further clarifies that except when deemed necessary, in principle, there is no requirement to conduct additional Japanese Phase 1 trials.