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.

According to the news article (アルツハイマー病治療薬「レケンビ」20日収載へ…ピーク時売り上げ986億円予測｜トピックス | AnswersNews (ten-navi.com)) released by AnswersNews date 13/Dec/2023, the National Health Insurance (NHI) drug price for “LEQEMBI” (lecanemab) has been set, using the cost accounting method, at 45,777 Japanese yen for a 200 mg 2 mL vial and 114,443 Japanese yen for a 500 mg 5 mL vial. The drug is administered at a dose of 10 mg per kg of body weight bi-weekly, and the annual drug cost for a patient weighing 50 kg would be approximately 2.98 million yen. The number of patients treated annually with “LEQEMBI” is expected to peak at 32,000. The peak sales are expected to reach 98.6 billion yen on an NHI price basis in the ninth year of its launch (i.e. FY2031). The NHI drug price calculation was based on the following factors: (1) the drug has a novel mechanism of action; (2) clinical trials have demonstrated clinically significant efficacy, even in patients who have had an inadequate response/refractory to existing treatments; and (3) it is the first drug that has been shown to inhibit the progression of dementia. As a result, a price premium for its usefulness was granted to LEQEMBI’s drug price.

The news “厚労省・城医薬局長　米バイオベンチャー誘致でドラッグ・ロス解消「まずは審査の誤解を解くところから」 | ニュース | ミクスOnline (mixonline.jp))” was released by MixOnline on 16/Nov/2023. The article discusses the efforts of Japan’s Ministry of Health, Labour and Welfare (MHLW) to attract U.S. biotech ventures to the Japanese market and mitigate the issue of drug lag/loss. Katsufumi Jo, Director of the Pharmaceutical Safety and Environmental Health Bureau at the MHLW, underscored the importance of dispelling misconceptions about Japan’s pharmaceutical regulatory and drug pricing systems, which have deterred these ventures from entering into the Japanese market. To bridge the gap in communication between Japanese regulatory agencies and global biotech companies, the MHLW plans to establish a representative office of the Pharmaceuticals and Medical Devices Agency (PMDA) in the U.S. to provide accurate information and consultations in English about Japan’s pharmaceutical regulations. This will enable regulatory consultations with PMDA in the U.S., including conducting clinical trials in Japan. The MHLW’s initiative to establish the PMDA’s U.S. office not only aims to reduce drug lag/loss but also seeks to position Japan as a more appealing and advantageous landscape for international biotech collaborations, ultimately benefiting the pharmaceutical landscape both domestically and internationally.