About 100 Million Yen to Administer “Luxtana”, Gene Therapy Drug, on Both Eyes

According to the news article“遺伝子治療薬「ルクスターナ」両目投与で約1億円…「リットフーロ」など30日薬価収載|トピックス | AnswersNews (ten-navi.com)” released by AnswersNews dated 23/Aug/2023, the Central Social Insurance Medical Council of Japan (Chu-I-Kyo) gave the green-light to the historically high listing price of “Luxturna”, a groundbreaking gene therapy drug developed by Novartis Pharma. Luxturna (generic name: Voretigene Neparvovec) will be used for the genetic treatment of “Inherited Retinal Dystrophy due to Biallelic RPE65 Mutations,” a hereditary eye disease. It functions by addressing the functional deficiency of the RPE65 gene. NHI price for reimbursement of the treatment is calculated using a cost-based method, and a single vial (0.5 mL) is priced at 49.6 million yen (about 350K USD), resulting in the total treatment costs for both eyes of nearly 100 million yen (about 700K USD). Luxturna is expected to reach 500 million yen (about 3,500K USD) in annual sales at its peak, with an estimated five patients receiving the treatment in Japan.

Discussion Just Started About Necessity of Japanese P1 Data to Initiate Global P3

According to the news article “薬事検討会 国際共同P3前に企業責任で複数人種での安全性確認を条件に「日本人P1データ不要」も一考 | ニュース | ミクスOnline (mixonline.jp)” released by MixOnline as of 08Aug2023, the study group operating under the Ministry of Health, Labour and Welfare discussed the necessity of conducting Japanese Phase 1 before Japan’s joining multi-regional clinical trials (MRCTs). Japanese Phase 1 trials were mandatory as of 2007, and a more flexible approach was introduced in 2014. However, there are still many cases where Japanese Phase 1 was required, and there is no clear understanding between the industry and the government regarding conditions where such a flexible approach is acceptable. This issue leads to delays in MRCTs in Japan and raises concerns about “drug loss” risks. Ei Narusawa (Professor at Kitasato University School of Pharmacy), a member of the study group, pointed out that verifying safety in the Japanese population should ideally be done in Phase 3 studies. He suggested, “If companies can thoroughly confirm that there is no difference in safety and PK profiles among different races before the initiation of Phase 3, it might be possible to propose a direction where Japanese Phase 1 is not necessarily required.” A PMDA’s executive officer said that though a definitive standard for deciding the necessity of these trials for the Japanese is complex, it’s feasible to outline the factors that should be considered when evaluating this necessity. Additionally, there were diverse suggestions to change the handling of orphan drugs and to clarify responses based on similar drugs, highlighting the necessity of defining the design of the regulatory framework.



Japan’s Initiative for Streamlined Orphan Drug Designation

According to the news article (厚労省・薬事検討会が議論開始  オーファン指定の基準明確化、早期化で「3割増」と試算 | ニュース | ミクスOnline (mixonline.jp)) released by MixOnline on 11th of July, 2023, the Ministry of Health, Labour and Welfare’s “Study Group on the Drug Regulatory System to Enhance Drug Discovery and Ensure Stable Supply” initiated discussions aimed at clarifying the criteria for designating. The committee broadly agreed to clarify the criteria and accelerate the designation of orphan drugs. The MHLW also estimates that clarifying the requirements for the designation would increase the number of orphan-designated drugs by about 30%. On the other hand, it was also proposed that priority review, one of the preferential measures for orphan designation, shouldn’t be applied to items subject to the relaxed requirements until the PMDA’s review system is fully expanded. The study group will summarize ideas by the end of the year or the end of the fiscal year (the end of March). The committee intends to implement those items that can be put into operation before the summary is announced and to make improvements through notices, Q&A, and any other means.

PMDA to Promote New Drug Developments in Japan by Raising Awareness among U.S. based Biotech Companies about Regulations in Japan

According to the news article “PMDA米国拠点、ラグ/ロス解消が使命  藤原理事長、日本の薬事制度を周知・浸透へ | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)” released by THE NIKKAN YAKUGYO on July 07, 2023, Yasuhiro Fujiwara, the President of the Pharmaceuticals and Medical Devices Agency (PMDA), has announced plans to establish their overseas operation bases in the United States and Asia to disseminate information about Japan’s pharmaceutical regulations. The US base aims to enhance collaboration between regulatory authorities in Japan and the United States, raise awareness of Japan’s pharmaceutical regulations among local companies and stimulate new drug development. This movement is also intended to diminish the “drug lag and loss” issue that is currently becoming a problem in Japan’s healthcare industry. These new overseas bases, planned for Washington, the US and Bangkok, Thailand, are set to start operations in the fiscal year 2024. While PMDA does not have a European base, they dispatch personnel to the European Medicines Agency (EMA) for information exchange. President Fujiwara expressed his intention to strengthen relationships through face-to-face meetings, acknowledging the time differences as a challenge. Furthermore, he emphasized the need for seamless transmission of vital information on Japanese pharmaceutical policies and guidelines to global stakeholders. This ensures more timely and effective communication for those involved in pharmaceutical development. The US base aims to showcase the appeal of Japan’s pharmaceutical regulations, attract the interest of US companies, and redirect their focus towards the Japanese market, thereby contributing to the resolution of “drug lag and loss in Japan.”

Japan will Remain the World’s Second Largest Market for New Drugs and Patented Drugs after the U.S. at least until 2027

As described in the news article “国内医療用医薬品市場 27年度まで5年平均成長率、特許期間中の市場はプラス6.5~7.5% IQVIA | ニュース | ミクスOnline (mixonline.jp)” released by MixOnline on June 26, 2023, IQVIA announced on June 23, 2023, the outlook for Japan’s pharmaceutical market for the fiscal year 2027. The compound annual growth rate (CAGR) of the pharmaceutical market segment which is under patent protection from 2022 to 2027, is projected to be between 6.5% and 7.5%, pushing the market segment up by 1.7 to 1.8 trillion Japanese yen (about 12 billion US dollars when the exchange rate for 1 US dollar is 145 yen) over the five years. Additionally, the market size of newly launched drugs from 2023 until 2027 is estimated to be around 1.1 to 1.2 trillion yen, contributing to an overall market expansion of 2.8 to 3.0 trillion yen (about 20 billion US dollars) when combined with patented drugs.

The report highlights the potential rise of Japan’s total pharmaceutical market, estimating it to reach the 11 trillion yen (about 76 billion US dollars) range by 2027, and Japan is described as the world’s second-largest market after the United States in terms of a market composed of new and patented drugs. The market driven by new and patented drugs will expand through biopharmaceuticals and specialty drugs, continuing to be an attractive market. However, for continued investment in new drug development in Japan, it was emphasized that “an environment that promotes innovation is essential.”

Recommendations by MHLW to Facilitate the Early Introduction of New Drugs in Japan

According to the news article, “有用性加算の柔軟化や類似薬拡大など提言  厚労省研究班、革新的新薬の早期導入で | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)” released by NIKKAN YAKUGYO on June 16th, 2023, the 2022 annual report compiled by the team of Ministry of Health, Labour and Welfare’s scientific research on “Appropriate Research on the Development Environment, Stable Supply, and Distribution Environment of Drugs” provided a comprehensive overview of the research related to maintaining and improving the appropriate development, stable supply, and distribution environment drugs.

The report presents specific recommendations aimed at facilitating the early introduction of new drugs. Firstly, the flexible application of the usefulness-addition criteria is proposed. The low application rate of usefulness addition is highlighted as a concern, particularly for orphan and pediatric drugs where conducting randomized controlled trials can be challenging. The proposal suggests evaluating the application of usefulness addition based on appropriate indirect comparison data. Furthermore, it emphasizes the importance of considering not only the primary evaluation parameters in clinical trials but also the patient’s quality of life and patient-reported outcomes.

The report also emphasizes the importance of ensuring predictability in drug pricing. To achieve this, the report suggests expanding the range and approach of similar efficacy comparison methods, enabling a more comprehensive selection of reference drugs (most similar drugs). It further advocates for enhancing the pre-consultation system regarding drug price calculation. Additionally, it recommends applying foreign average price adjustment even for price increases after listing and considering additional add-ons for products with simultaneous launches in Japan, Europe and the United States.

“Increase Biosimilars with Over 80% Market Share to 60%” New Goal to Promote Biosimilars in Japan

According to the news (バイオシミラー普及へ「シェア80%超成分を6割に」の新目標、市場拡大元年となるか | AnswersNews (ten-navi.com)) released by Answers as date of 05/06/2023, the Ministry of Health, Labour and Welfare has set a goal for disseminating biosimilars (BS). By the end of the fiscal year 2029, they aim to increase the replacement rate of reference products to BS, of which market share exceeds 80%, to 60% on a quantity basis. Currently, 16 ingredients of BS have been approved, but only three ingredients, epoetin-α, filgrastim and darbepoetin-α, representing less than 20%, have achieved a quantity share of 80% or more. It is said that the dissemination of BS will take time and may follow a similar path as generic drugs. While concerns about quality are settling down, there is still a lack of stability in the supply of imported products, and cases of shipment adjustments and suspensions exist. Currently, only three ingredients exceed a quantity share of 80%, and there are challenges in increasing the percentage of those ingredients. The introduction of authorized generics (AG) has quickly increased the overall share of BS, but price competition has eroded companies’ financial strength, posing challenges for investment recovery and supply continuity. Cost-effectiveness is crucial for achieving the government’s target, and companies with a consistent system from in-house manufacturing to sales can reduce costs. However, sourcing from other companies may take time to secure profits. To promote wider dissemination, incentives in the medical fee reimbursement system and alleviation of economic burdens are necessary, but the previous policies have not yielded satisfactory results. Ensuring a stable supply is also essential, as it becomes difficult to gain the trust of physicians and patients in situations of supply instability. The dissemination of BS is still in its early stages and faces various challenges to be addressed.

Japanese Pharmaceutical Market in the FY 2022 to Reach a Record High of 10.97 Trillion Yen

According to the news article “2022年度の国内医薬品市場、過去最高の10.97兆円…前年度比2.6%増、コロナ薬・診断薬伸びる | AnswersNews (ten-navi.com)” released by AnswersNews on June 1st, 2023, IQVIA announced that the pharmaceutical market in Japan reached a record high in the fiscal year 2022, with a 2.6% increase from the previous year, totaling 10 trillion and 969 billion yen (approximately 80 billion USD at the current exchange rate). The demand for therapeutics and diagnostics for the treatment of COVID-19 contributed to this growth. Ono Pharmaceutical’s immune checkpoint inhibitor drug, “Opdivo,” remained at the top for the second consecutive year in product sales. All three market segments, including hospitals, clinics, and pharmacies, experienced growth. Among therapeutic categories, “anti-tumor agents” generated the highest revenue. The COVID-19 pandemic also led to a significant increase in demand for diagnostic test reagents, propelling them to the top 10 therapeutic categories. From January to March 2023, the market recorded a 1.3% increase, reaching 2 trillion and 591 million yen (approximately 20 billion USD), while diagnostic test reagents experienced a substantial decrease. In terms of product sales, “Opdivo” maintained its top position, followed by “Keytruda” and “Eliquis.” Among the pharmaceutical companies, Chugai Pharmaceutical retained its leading position, followed by Takeda Pharmaceutical and AstraZeneca.

Regulatory Requirements and Drug Prices of Biosimilars in Japan

As explained in the article, “バイオシミラー|AnswersNews Plus (ten-navi.com)” released by AnswersNews on November 21, 2018, a biosimilar is a drug with the same quality, safety, and efficacy as a reference biopharmaceutical product. It is developed by a different company (not the company that is marketing the originator) after the patent for the reference product has expired. To demonstrate clinical equivalence and similarity to the reference product, clinical trials enrolling actual patients are required even if the development process of biosimilars is not equivalent to that of the reference product. The price of a biosimilar is typically higher than that of a typical generic product due to the high costs associated with development and manufacturing. However, it is typically 70% of the price of the reference biopharmaceutical product. For subsequent biosimilars, the price tends to be proportional to the price of biosimilars already on the market. And also, current updates on government policy indicate a supportive trend for biosimilars.

SAKIGAKE Designation System in Japan (similar to Fast Track/Breakthrough Therapy in the US)

As described in the article “先駆け審査指定制度|AnswersNews Plus (ten-navi.com)” released by AnswersNews on 15/03/2019, the SAKIGAKE designation system is a program that grants preferential treatment to innovative products such as pharmaceuticals, medical devices, regenerative medicine products, and in vitro diagnostic drugs that are applied for approval in Japan for the first time in the world. This system shortens the standard 12-month approval period to 6 months for designated products. To be designated as a target product, it is necessary to demonstrate the ground-breaking nature of the product, the severity of the targeted disease, extremely high efficacy, and an intention to develop and apply early in Japan. The SAKIGAKE designation system provides preferential measures such as advancing the approval review process, prioritizing review, consultation on development progress management, and extending re-examination periods. In addition, a “SAKIGAKE designation system addition” is added to the drug price of target products as a premium, which serves as an incentive for drug development.