Mini Review
Future vision of the healthcare innovation ecosystem in Japan and expectations for drug discovery in academia
2023 Volume 5 Issue 3 Pages 53-56
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2023 Volume 5 Issue 3 Pages 53-56
The Federation of Pharmaceutical Manufacturers’ Associations of Japan (FPMAJ) is a federation consisting of regional associations and industry-specific associations whose members are pharmaceutical manufacturers. FPMAJ conducts investigation research of matters necessary for the development of the pharmaceutical industry and summarizes and works to realize the opinions of the industry. At the same time, FPMAJ aims to promote common benefits of member organizations and to contribute to the development of the pharmaceutical industry as well as the improvement of the people’s lives.
The ideal vision of the pharmaceutical industry is to contribute to the extension of the healthy life expectancy of the people and to drive the growth of the Japanese economy as a core industry. The pharmaceutical industry has contributed significantly to improving patient satisfaction through the creation of innovative new drugs by achieving drastic therapeutic effects such as cure/remission of disease and relief of symptoms for HIV/AIDS, hepatitis C, rheumatism, and cancer for which effective therapeutic drugs were scarce.
Technologies and methodologies related to drug discovery are becoming more diversified and sophisticated. Drastic advance in biotechnology has led to the emergence of diverse modalities, such as cell therapy, gene therapy, and oligonucleotide therapy, in addition to small molecule drugs. That made it possible to develop drugs for rare and intractable diseases that previously could not approached and offer new therapeutic options to patients. In addition, the business model of the pharmaceutical industry is shifting from a “vertical integration” model in which entire value chain, from R&D to sales, is conducted in-house to a “horizontal specialization” model in which the pharmaceutical industry collaborates with companies, that have strengths in diverse fields that have become more sophisticated, complex, and specialized due to advances in IT and digital technology, in each stage of value chain (Fig. 1). In particular, cooperation with biotech startups and academia are essential for the creation of drug seeds, and 80% of the new drugs under development in the world account for by biotech startups. Especially many of the novel modalities including antibody, gene therapy, and cell therapy, are originated from startups, which are now indispensable for drug development [1].
“Horizontal specialization” value chain in which companies with strengths in diverse fields collaborate. DTX: digital therapeutics; RWD: real-world data; CRO: contract research organization; CDMO: contract development and manufacturing organization; API: application programming interfaces.
So far, the value chain of drug development has been completed by a single pharmaceutical company. As mentioned above, however, the difficulty of drug discovery has increased, and new modalities have emerged one after another, and open innovation where collaborate with diverse companies, has become the mainstream. Thus, various innovations are occurring. In the drug discovery research, it becomes an era in which AI and robotics are active, and not only speed but also success rate is expected to improve. It is expected that the quantum computer will also be utilized in the future, and further detailed analysis will be possible. Various designs have also been generated for clinical trials, including adaptive design, umbrella trial and basket trial [2, 3], with the aim of improving the efficiency and probability of success of clinical trials. In addition, the environmental improvement for Decentralized Clinical Trials (DCT) has also greatly progressed, as the risk of virus infection makes it difficult to come to the hospital under the COVID-19 pandemic. Further innovation is expected in the future using Real World Data (RWD) for stratifying the participants, using as a control group in clinical trials and utilize for the addition of a new therapeutic indication. Also, the COVID-19 pandemic also raised awareness of how to get the therapeutic drugs and vaccines can be delivered to patients as quickly as possible while balancing efficacy and safety. That led to the discussion on how to approve drugs in emergency situations, as the results, Special Approval for Emergency was established in the amendment of the Pharmaceutical and Medical Devices Act (PMD Act) in May 2022 [4]. Subsequently, the first domestically-developed COVID-19 drug (Xocova Tablet 125 mg) was approved under this emergency approval system [5]. As for drug manufacturing, biopharmaceuticals require huge investment in their production compared with the conventional low-molecular-weight compounds. As a recent case, a few hundred-billion-yen investment was made for the improvement of a manufacturing facility. In drug discovery of new modalities, while small-scale biotech startups generate the drug seeds, a huge amount of capital investment requires for manufacturing them. Therefore, the business of Contract Manufacturing Organization (CMO) and Contract Development and Manufacturing Organization (CDMO) is expanding, and horizontal specialization is progressing in the field of drug manufacturing. As an innovation in medical services and pharmaceutical distribution, China has built a one-stop healthcare platform that covers telemedicine, online pharmacies, and drug delivery. In order to improve the reliability of telemedicine, patients themselves can select a physician and same-day or next-day drug delivery is possible by utilizing drones and driverless delivery tracks. Because of the differences in the regulatory environment, it is difficult to introduce such a system entirely in Japan at present, but it is anticipated that the reform of drug distribution using such innovative technologies will gradually occur. Finally, utilization of healthcare big data is essential for value chain innovation such as drug discovery research, clinical development, and post-marketing surveillance, and the discussion is currently ongoing about efficient clinical data collection and utilization in healthcare, as well as secondary use. In Europe, the advanced concept of European Health Data Space (EHDS) has been proposed. By reference to EHDS, I believe that Japan should advance the comprehensive policies centered on both “data-base construction” and “improvement of the legal system” by backcasting from the perspective of what kind of benefits can be provided to the people.
Academia’s research results are licensed out to biotech startups or pharmaceutical companies, which proceed to clinical trials, approval application, and launch into the market. It requires more than 10 years and huge R&D budget to develop a novel drug, still, many drug seeds end in failure without reaching approval. In the course of the academia’s drug seeds are applied practically by pharmaceutical companies, there are various challenges including the fostering of biotech startups. First, I will discuss drug discovery research by academia. From the viewpoint of pharmaceutical companies, a major issue is the lack of data necessary for drug discovery. Pharmaceutical companies cannot decide to introduce the compound or biologics based solely on a certain level of efficacy in an experimental model. For introducing the compound or biologics finding at academia to the pharmaceutical company, the compound or biologic must be carefully examined from various perspectives, such as which biomolecule in the organism the compound or biologic binds on (identification of the drug target molecule), whether the compound or biologic does not work on non-drug target molecules other than the drug target molecule (specificity to drug target molecule), whether the drug target molecule is also expressed in the human organism, whether there is any safety concerns about acting on the drug target molecule, whether the used experimental model reflects the human disease, and whether the compound or biologic accesses the target tissue with clinically acceptable route and dose of administration. Therefore, in seeking out-licensing to pharmaceutical companies, it is important to acquire as much data as possible to answer these questions. In addition, the patent is very important in the social implementation, however, there is a discrepancy between academia and the industry in the way of thinking about patents. When significant results are obtained in basic research, it is important to aim for making presentations in academic conferences and submitting scientific research papers as early as possible, but appropriate patent strategy is necessary for the practical application. The patent strategy including the timing and countries of filing, the scope of the claims, and the implementation examples is very difficult to determine, therefore, it is important to consult an expert at an early stage. Pharmaceutical companies will be forced to give up licensing-in, if there are problems such as cannot obtain a patent or can only exercise rights to a limited extent due to a paper having already been published.
Finally, a major concern for Japan as a whole is the lack of important resources, called assets such as ideas and new substances, in Japanese academia. In fact, in terms of the ranking of the number of papers published in major journals, as one of the indicators of basic research, Japanʼs ranking has been declining since over the past 20 years, while China ranked number one in the world, overtook the United States [6]. I believe that investments in basic research must be spared in order to continuously generate innovative drug seeds from Japan in the future.
Biotech startups play an important role in the development of drug seeds for so-called novel modalities such as antibodies, gene therapy, and cell therapy. However, a survey of the clinical development status of these new modalities by company and by nationality revealed that most of the products were from overseas bio-startups, while those from Japanese start-ups were very few. Another survey about unicorn companies, which are privately held startup companies with a value of over $1 billion, showed that many startup companies across the world, led by the United States, followed by China, India, and European countries, have achieved success, while number of successful Japanese companies are very small. Furthermore, a survey of M&A as an exit strategy for startups in Japan by industrial field have reported that there are many M&As in IT related field such as mobile and cloud, but very few in the life science field [7].
Challenges related to starting and fostering Japanese startups include a lack of investment funds, low level of entrepreneurship, a lack of professional human resources, and a delay in globalization. In terms of investment capital, the gap between Japan and the United States is more than 100 times larger in total investment, and the average investment per company in Japanese startups is only a fraction of that in the United States. In terms of the professional human resources, it is clear that the biotech startups require advanced talents with expertise in science and business and, at the same time, having experience in R&D at pharmaceutical companies. When compared Japan with Europe, the United States, Korea, and Taiwan, it became clear that Japanese startups cannot secure enough percentages of human resources of any of PhD and MD scientists, the talent with experience with pharmaceutical companies and MBA holders.
According to the results of the Japanese awareness survey on starting new business, the proportion of people planning new business is extremely low compared to other developed countries, and the proportion of people who believe that starting a new business is a desirable option is also very low in Japan.
In order for various players such as academia, startups, and pharmaceutical companies to work together and lead the drug seeds generated by basic research to the creation of innovative new drugs, building a drug discovery ecosystem constructed by a wide range of stakeholders from industry, academia, and government is necessary.
Currently, Japanese government proceeds various projects such as Medical Innovation Support Office (MEDISO) and Healthcare Innovation Hub (InnoHub) to support drug discovery by academia and startups. By utilizing such projects from the early stage, useful advice and support will be expected. In addition, the possibility of receiving financial support is expanding through Japan Agency for Medical Research and Development (AMED) which promotes R&D for the practical application of medical products. Especially, a huge budget of 300 billion-yen was decided to be allocated to support biotech startups as “Strengthening Program for Pharmaceutical Startup Ecosystem” in December 2022. Also, based on the government’s “Bio-Strategy 2020”, Greater Tokyo Biocommunity (GTB) and Biocommunity Kansai (BiocK) were certified by Cabinet Office as the foundations of an ecosystem aiming to form a global bio-community. The pharmaceutical industry intends to actively commit to these activities in order to strengthen cooperation among industry, academia, and government in the bio-community.
As the first initiative, the Japan Pharmaceutical Manufacturers Association (JPMA), which is a member of FPMAJ, participates in the management of the GTB Tokyo metropolitan area, Hongo-Ochanomizu-Tokyo station bases, as one of the secretariats. In September 2022, a kick-off meeting was held to strengthen cooperation by three secretariats of the area, which are the University of Tokyo, Tokyo Medical and Dental University, and JPMA. The first general meeting was held in March 2023, and currently many organizations from academia and the pharmaceutical industry are participating.
To implement highly promising drug seeds as innovative new drugs in society, it is necessary to have human resources to drive the ecosystem in addition to funds and facilities. The government is supporting to develop biopharmaceutical manufacturing sites through projects such as the “Strategy for Strengthening the Vaccine Development and Production System”. As for JPMA, we believe that human resources who operates facilities are crucial and support activities of the Biologics Center for Research and Training (BCRET) as well as the development of industry ready-to-work biomanufacturing human resources and the education of students in biomanufacturing human resources. JPMA also assists the “Support Program for Biostatisticians / Project Promoting Clinical Trials for Development of New Drugs and Medical Devices”, by AMED, with the aim of fostering biostatisticians who are essential to advance clinical research.
I believe that the pharmaceutical industry should commit not only exit strategies, but also the formation of a drug discovery ecosystem in which academia’s drug seeds are smoothly brought into practical application through various initiatives such as formation of bio-community and fostering human resources. Consequently, industry, government, and academia collaborate together to continuously generate innovative healthcare solutions and contribute to the improvement of human healthcare as well as the revitalization of Japan as a world-leader in science and technology.
