Topics Held the 32nd Pharmaceutical Association of Japan Policy Seminar Contribution of Innovation for Patients: Drug Discovery in the With COVID-19 Era

Molecule by Molecule Measurement Contribution to Pharmaceutical Science

In the world of pharmaceutical sciences, including drug discovery, a wide variety of analytical instruments and techniques are used. The field of mass spectrometry, in which I have been involved for many years and which led to my winning of the Nobel Prize in Chemistry in 2002, is no exception.

Mass spectrometry is a method of ionizing molecules of a few nanometers (a nano is one billionth of a meter), which are invisible even with a microscope, and measuring their mass one by one. Ions accelerated by an electric field move according to their weight and charge. Therefore, by measuring the time it takes for the ions to reach the detector, the mass can be derived. The sample to be analyzed usually contains several kinds of molecules. Therefore, the resulting graph shows the "detected molecules" on the horizontal axis in order of mass, and the "amount" of each substance on the vertical axis as relative intensity. This is called a mass spectrum.

The Cancer Genome Information Management Center (C-CAT) was established in June 2018 to realize high-quality cancer genome medicine in Japan. Cancer genomic medicine refers to the medical practice of examining the genome of a patient's cancer cells, capturing genetic abnormalities, optimizing treatment, predicting prognosis, and preventing disease onset.

One of C-CAT's specific initiatives is the promotion of the "Cancer Gene Panel Test. In this test, several hundred gene mutations are examined at once to identify genes involved in cancer development. The results are analyzed by an "expert panel," consisting of experts in cancer treatment and pharmacotherapy, and are returned to the medical practice in the form of a report. The physician in charge of the patient then considers the optimal treatment plan based on this report.

This type of cancer genome medicine is currently available at a total of 206 medical institutions nationwide, including 12 core hospitals for cancer genome medicine, under the universal health insurance system.

On the other hand, the data obtained from the test, together with clinical information collected at the hospital, is processed into a form that does not identify individuals. With the consent of the patient, the data will be stored in C-CAT's "Cancer Genome Information Repository" and used to develop new treatments and diagnostic methods.

Data from the repository will also be stored in the Cancer Knowledge Database (CKDB), which is being maintained by C-CAT, and will be used as basic data for examination by the expert panel. In addition, the CKDB will also collect information on the latest publications, clinical trials, drugs, and marker evidence. These are updated on a monthly basis by a curatorial team of specialists in oncology and other fields.

Even if a genetic abnormality is found by the cancer gene panel test, some patients may not be able to use existing drugs that target the genetic abnormality because they are not covered by the existing drugs. In such cases, one option is to use the "catch-up test" system. This system is a public means of enabling the use of drugs that are not covered by the existing drugs if they are expected to be effective, and has already been used by more than 100 patients.

Tohoku University Tohoku Medical Megabank Organization (ToMMo) was established in 2012 with the aim of realizing future-oriented medicine centered on personalized medicine and personalized prevention.

One of ToMMo's challenges for future medicine is the "genome cohort study. The word "cohort" means a group, and ToMMo is conducting a "community cohort study" for people living in the areas affected by the Great East Japan Earthquake and a "three-generation cohort study" for genetically inherited family members. The data collected will be utilized as evidence for futuristic medicine. In this survey, the general population is recruited, biological samples are collected, and health surveys, such as disease incidence, are conducted over several decades. The main feature of the survey is that it is a "prospective" survey that moves forward from a healthy state into the future. Unlike surveys that collect patients who have already been diagnosed with a disease and look back into the past, the major advantage of this method is that it can search for subtle signs before the onset of a disease. Specific target diseases include cancer, cardiovascular disorders, diabetes, dementia, and psychiatric disorders among adults. Currently, approximately 84,000 people are participating in the community cohort study and 73,000 people are participating in the three-generation cohort study.

Another challenge for ToMMo is the establishment of a "composite biobank. The biobank will store a vast amount of biological samples and information collected through the cohort study, as well as analyze and convert them into data, which will be stored and accumulated in the biobank as well. The biobank can be utilized from the biobank of the Organization, and at present, more than 50 cases have already been distributed and more than 140 collaborative studies have been conducted. By converting biospecimens into data and then distributing them to users, the depletion of the limited supply of biospecimens can be prevented. The biobank's "composite" name is due to the fact that the analysis center is located within the bank.

ToMMo has also developed the "Japonica Array (R)," a genetic analysis tool that can analyze Japanese genome information with high accuracy and at low cost. It is hoped that this tool will be used by health checkup centers nationwide to promote personalized medicine and prevention in Japan.

Genome-based medicine will surely become the foundation of Japanese medicine. It is with this strong belief that we have been working on the genome medicine policy.

Thanks to our efforts, in June 2019, the "Basic Policies for Economic and Fiscal Management and Reform" (Kotta-no Mukoshi) clearly stated the promotion of genomic medicine, and the "Action Plan for Whole Genome Analysis" was presented at the end of the same year. I would like to emphasize that we chose whole genome analysis instead of exome analysis.

Only 1 to 1.5% of the entire genome, or exons, contain the protein design code. Therefore, in other countries, priority has been given to exome analysis, which examines only the exonic regions. Recently, however, it has become clear that regions other than exons, whose roles have been unknown, are also involved in the regulation of protein expression and the causes of disease. We believe that the systematic understanding of the entire genome and the full scope of heredity and disease will lead to major innovations in the future, and this project is now underway.

Meanwhile, the information retrieval system "CANNDs" is the foundation for utilizing the collected data. This system will contain clinical data as well as genome information, and will be widely used as public property. Until now, such medical data has been collected on a research-by-research basis, and consent for its use has been obtained from each patient. With CANNDs, a review committee will collectively obtain permission for use. We expect active utilization of data by academia as well as pharmaceutical companies.

Another important issue in the promotion of genomic medicine is ELSI (Ethical, Legal, and Social Issues). For example, there are no clear rules in Japan for returning the results of a patient's genome analysis to the patient. Also, what should be done to resolve any discrimination or misunderstanding that may arise when people other than the patient themselves become aware of such data? The development of an environment that provides the foundation for such a solution is an urgent issue for us.

The ratio of R&D expenses to net sales in the pharmaceutical industry is approximately 11%, which is outstandingly high compared to the average of approximately 4% in other manufacturing industries. The development of pharmaceuticals requires many years and large amounts of money, and this trend has intensified in recent years. In order to promote drug development, support is needed at various stages, from basic to actual clinical development.

On the other hand, the national healthcare expenditure has been soaring year after year and currently exceeds 40 trillion yen annually. In addition, the ratio of national medical expenses to national income is close to 11%. Japan's basic policy has been to provide insurance coverage for all medical treatment that has been confirmed to be effective and safe, and that is truly necessary and appropriate for the patient. However, considering the future aging of the population and the decrease in the working-age population, it must be said that stable operation of this medical insurance system will be extremely difficult. Under these circumstances, the Ministry of Health, Labor and Welfare (MHLW) introduced in 2006 the "Cost-Effectiveness Evaluation of Pharmaceuticals and Medical Devices," a system to reflect the cost-effectiveness of pharmaceuticals and medical devices in NHI prices. Prices are adjusted based on this evaluation.

We ask, "What is the purpose of medical insurance?" and "What stance should we take in maintaining the system in the future? and "What stance should we take in maintaining the system in the future?

Japan has a system in which most pharmaceuticals approved by the pharmaceutical affairs bodies are reimbursed by insurance. On the other hand, there are countries around the world that use cost-effectiveness evaluations to decide whether a drug should be covered by insurance. Also, if the insurance system is for hedging economic risks, then a higher percentage of medical costs can be covered by insurance when the medical costs are high, and a lower percentage can be covered by insurance for those that are not. The current high-cost medical fee system is similar to this idea.

Regardless of which measure is adopted, it will be difficult to proceed overnight, as it will require a major change in Japan's existing medical insurance system. It will be important to stimulate discussion and deepen public understanding. We have been discussing the question, "Is it possible to balance innovation in drug discovery and the stable operation of the medical insurance system? Rather, we must proceed with future efforts based on the idea that they must be compatible.

The concerns of patients undergoing treatment are not limited to medical problems such as treatment, side effects, and aftereffects. Many patients have social or economic concerns.

For workers with diseases, especially cancer, support for "balancing treatment and work" has been provided for the past decade. However, even today, 20% of those diagnosed with cancer are forced to quit their jobs, and 20% are unable to return to work even after treatment has restored their ability to work. It is estimated that the annual loss to Japanese society due to such labor losses exceeds 1 trillion yen. In addition, statistics show that 4.9% of cancer patients have changed or given up treatment due to the burden of treatment costs. In addition, among younger cancer patients, about 33% had to dip into their savings to pay for treatment, and about 17% received financial assistance from relatives or strangers.

Innovation in medicine tends to focus on innovative treatment effects, but when considering the needs of patients, we should not only look for ways to save their lives, but also for ways to make the most of them socially and improve the quality and quantity of their lives. And this will enhance the vitality of Japanese society and lead to further innovation.

On the other hand, one of the needs of society as a whole with regard to healthcare is to maintain a healthcare system that provides peace of mind to the people. Currently, Japan's national healthcare expenditure exceeds 43 trillion yen. We, the patients' association, are asking for new drugs to be covered by insurance, but on the other hand, this will lead to an increase in social security costs. It is good that cancer treatment is advancing, but it is a challenge to compete with patients with other diseases for budgets and to become a burden on them.

In the UK, the National Institute for Health and Care Excellence (NICE) decides by consensus the scope of medical care covered by insurance. The council includes 20 people, including experts, media, pharmaceutical companies, citizens, patients, and NICE staff. What is important is that a social consensus is formed here. In Japan, however, patients do not participate in these discussions. Japan should establish a system that allows patients' voices to be heard in the calculation of drug prices and the inclusion of medical care in insurance coverage.

The quality of medical care should be improved, and the period of healthy life should be prolonged. We are currently working on three issues to bring about innovation in drug discovery for this purpose.

The first is to elucidate the mechanisms of disease onset and progression. If this can be achieved, it will be possible to predict the future onset of disease in currently healthy people and to intervene at an early stage with preemptive medicine. We will be able to set the field of preemptive medicine as a new target and develop therapeutics and diagnostics.

The second issue is the accumulation of data for the "elucidation of the mechanisms of disease onset and progression" mentioned in the first issue, and the establishment of a system to utilize this data. In particular, "genomic information combined with clinical information" and "omics data, which is comprehensive information on proteins in the body," are needed. It is also important to have data not only during the onset of a disease, but also before the onset and after recovery. An environment for the utilization of this data must be created. This is the realization of digital transformation (DX) in healthcare.

The third is the creation of an ecosystem to create innovative new drugs through the circulation of human resources, funds, technological innovation, knowledge, and information, in collaboration not only with academia, venture companies, and pharmaceutical companies, but also with medical institutions, regulatory authorities, and investors.

In addition, countermeasures against infectious diseases must be taken from ordinary times. AMR (drug resistance), which is expected to cause 10 million deaths per year by 2050 if no action is taken, is an important issue, but a list of problematic strains has already been compiled, and prioritizing research and development of new drugs for these strains will prevent it from becoming a serious social problem. It is necessary to establish a cycle in which research and development of antimicrobial agents is continuously produced through pull-type incentives and other policies.

Drug discovery innovation will lead to increased healthy life expectancy, which in turn will lead to an increase in the workforce, a positive impact on the economy, and an improvement in the burden of healthcare costs. This will lead to another round of drug discovery innovation. We hope that such a virtuous cycle, the "Angel Cycle," will be born.