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- 2026-05-19 17:47:13
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- Mavenclad can be prescribed at general hospitals
- by Eo, Yun-Ho Jan 19, 2021 06:02am
- New multiple sclerosis drug Mavenclad can be prescribed in general hospitals According to related industries, highly active recurrent multiple sclerosis treatment Mavenclad (Cladribine) by Merck has now passed the drug commitee (DC) of SMC, AMC, Shinchon Severance Hospital, and NCC. Mavenclad is the first short-term oral treatment that has shown a significant overall effect in terms of the degree of physical disability progression, annual recurrence rate, number of active lesions shown on MRI, and major disease activity indicators in patients with recurrent multiple sclerosis. Mavenclad's clinical trial program included long-term follow-up data from the 8-year prospective observational registry PREMIERE study, along with the CLARITY Phase 3 study and CLARITY EXTENSION, ORACLE MS, and ONWARD Phase 2 study corresponding to the CLARITY expanded clinical trial. As a result of post-hoc analysis of patients with high disease activity in the CLARITY 2,3 study conducted for two years, the annual recurrence rate of patients receiving Mavenclad decreased by 67%, and the Extended Disability Status Scale (EDSS), which indicates the degree of disability progression. Also, Mavenclad administration group showed a 82% decrease compared to the control group. However, Mavenclad’s significant adverse reactions are lymphopenia and shingles. The lymphocyte count of patients must be measured before and during Mavenclad administration to patients with multiple sclerosis. It is contraindicated in certain populations, including patients with impaired immune function and pregnant women. Seongmin Kim, Professor of Neurology, SNUH said, "Multiple sclerosis is a chronic inflammatory demyelinating disease that occurs in the central nervous system such as the brain and spinal cord. If not treated, symptoms may worsen and sequelae such as severe disorders may remain, so a new treatment option with high convenience is available. It was a necessary situation. Mavenclad can be taken orally and can help improve the quality of life for patients in that it provides lasting effects for 4 years with only short-term treatment of up to 20 days."
- Company
- Big Pharmas busy reaching out for KRAS targeted therapy
- by Kim, Jin-Gu Jan 18, 2021 06:14am
- Global pharmaceutical giants are eager to develop targeted therapy for ‘Kirsten rat sarcoma viral oncogene homolog (KRAS)’ mutation, initially considered as an impenetrable technology for last four decades. Apparently, KRAS mutation is found in about one out of four cancer types. Specifically, the mutation is frequently found in cancer types with bad prognosis like lung cancer, colon cancer and pancreatic cancer. Pioneered by Amgen, small and big companies like Novartis, Sanofi, Bayer, Boehringer Ingelheim, Merck and Mirati Therapeutics are fiercely competing against each other to dominate the blue ocean. ◆Why did MSD bet USD 2.5 billion on candidate medicine in preclinical trial phase? On Jan. 13 (local time), MSD exclusively licensed-in an anticancer candidate medicine targeting KRAS from Japanese-based Otsuka Pharmaceutical’s subsidiaries, Taiho and Astex. MSD has agreed to pay maximum 2.5 billion dollars (approximately 2.75 trillion won) including an upfront payment of 50 million dollars (approximately 55 billion won). To win the competition against Revolution Medicines, Boehringer Ingelheim decided to put forth a colossal bet. The reason behind MSD’s massive payment for a candidate medicine at a preclinical trial level coincides with the recent global pharmaceutical industry trend. Lately, the global pharmaceutical industry is hectic with KRAS targeted therapy R&D. Although the technology was thought to be impossible to crack for last 40 years, KRAS targeted therapy nabbed the Big Pharmas’ attention after Amgen showed the possibility in the commercialization in 2019. ◆40 years of going nowhere, KRAS targeted therapy results in a first clinical findings in 2019 KRAS is one of factors that cause cancer. KRAS activates transmission of signals from the cell surface receptor to the nucleus. It is at the same level as anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), which already have developed targeted therapy for. It is actually the first cancer-causing gene the human race has discovered. But since the first discovery in 1982, the relevant treatment development was sluggish for four decades. Compared to other cancer-forming genes, KRAS has more frequent mutations and transforms the protein structure into a wide array of variations. And it has been hindering the targeted therapy development until lately. The frequency is apparently high for the KRAS mutation causing a number of lethal cancers like lung cancer, colon cancer and pancreatic cancer. And vast amount of researches were done to study the gene, but all of them failed at the end. In 2013, however, a group of researchers at University of California found a groundbreaking discovery of ‘binding pockets.’ Since then it was picked up as a candidate medicine and its first clinical findings were announced in 2019 after completing the preclinical phase. ◆Amgen takes the lead in R&D, sotorasib initiates Phase III clinical trial First, it was Amgen who presented the clinical results. AMG-510, also known as sotorasib, is evaluated as a frontier among the KRAS targeted therapy candidates. The Phase I clinical trial kicked off from August 2018. The result of the trial was unveiled at the 2019 International Association for the Study of Lung Cancer (IASLC). Cancer patients with non-small cancer lung cancer (NSCLC), colon cancer or pancreatic cancer showing KRAS mutation participated in the clinical trial. Five out of ten NSCLCL patients in the study had the KRAS mutation. A Phase II clinical trial, unveiled at the European Society for Medical Oncology conference last year, also demonstrated positive results. After using sotorasib in 53 patients with NSCLC, their progression-free survival (PFS) marked 6.3 months while the response rate reached 32.2 percent. Amgen is still currently conducting the Phase III trial that compares the drug against cell-killing chemotherapy docetaxel. In late last year, the U.S. Food and Drug Administration (FDA) designated the investigational drug as a Breakthrough Therapy. Besides the AMG-510 single therapy, the company is also running a clinical trial on a combination therapy with other various anticancer treatments. The drug is likely to get approval within this year at earliest. ◆Mirati, Sanofi, Novartis, Boehringer, Moderna and Bayer all on board Mirati Therapeutics is following Amgen closely. The company kicked off the clinical trial in January 2019, and now MRTX849 is in process of running a Phase 1/2 study. The Phase II interim analysis was disclosed late last year. The objective response rate (ORR) in 51 patients with NSCLC marked 45 percent. The company aims for the FDA approval in the latter half of the year. Moreover, Sanofi and Revolution Medicine are collaborating together on developing RMC-4630 since June 2019. In a partnership with Araxes Pharma, Johnson and Johnson started a clinical study on ARS-3248 from July 2019. Eli Lilly initiated the clinical trial on LY3499446 in November 2019. Last year, Mirati and Novartis started working on another candidate medicine TNO155, and its Phase 1/2 clinical trial began from last April. Navire Pharma and Erasca respectively started Phase I trial on BBP-398 in last August and Phase I trial on ERAS-601 in last December. Even more companies like Boehringer Ingelheim, Bayer, Moderna, Merck and Jacobio Pharmaceuticals are now into seeking KRAS targeted therapy with preclinical trial ongoing. In South Korea, Orum Therapeutics is reportedly exploring KRAS related R&D
- Policy
- 68% to “wait and see” before COVID-19 vaccination
- by Jan 18, 2021 06:14am
- Sandra Lindsay, a nurse in the U.S., is taking the COVDI-19 vaccine (Source: CNN). Apparently, six out of 10 people in South Korea are intending to ‘get inoculated after confirming the outcome’ of the COVID-19 vaccine. Only 28.6 percent answered they would ‘get inoculated as soon as possible.’ As requested by a public survey research firm KSTAT Research, Professor You Myung Soon at Seoul National University Graduate School of Public Health surveyed 1,094 adults around the country from Jan. 8 through 10 for the 11th survey on their perception of COVID-19. The study found 67.7 percent would wait until later to see the performance of the vaccine to take the vaccine. Regarding the timing of initiating the inoculation in South Korea, 59.9 percent said they should wait and see, while 37.8 percent said as soon as possible. On the questionnaire asking about the fear and anticipation of the vaccine, 40.4 percent said they have a same level of both fear and anticipation, when 28.1 percent have more fear and 25.6 percent have more anticipation. 42. percent expects the timing of the vaccine commercialization would be around the middle of the year, and 35.4 percent and 11.2 percent answered late this year and next year, respectively. The majority of the survey participants, or 80.3 percent of them said they intend to receive free safety-proven vaccine (53.2 percent maybe, 27.1 percent absolutely). Professor You Myung Soon noted, “The survey provided an insight into the people’s sense of threat by the COVID-19 pandemic, prudence in vaccine development and use, and a positive level of trust in the healthcare system and the government’s vaccination plan. The government would need to endeavor to reflect the people’s intention and experience from various angle based on the understanding that their final judgment would be comprehensively made.” The survey participants answered the South Korean society in last 12 months of COVID-19 was not safe (59.7 percent), average (29.2 percent), and safe (11.2 percent). The ratio of the participants answering ‘not safe’ peaked from the entire series of the COVID-19 surveys Professor You has done so far. Regarding the third wave of the pandemic, 51.9 percent said the worst has yet to come, whereas 23.8 percent said the worst has passed. The participants also scored average 40 assessing if the daily life has recovered from the changes COVID-19 brought, when 100 indicates ‘completely.’ However, the score was lower in different demographics, such as the low income community (35.4), unemployed (35.5) and women in 30s (35.3).
- Policy
- Celltrion announced results of external clinical trials
- by Lee, Tak-Sun Jan 18, 2021 06:13am
- The MFDS will hold a verification advisory group meeting on the 17th to evaluate the appropriateness of the clinical trial results for COVID-19 treatment Rekirona developed by Celltrion. And it plans to announce the results on the 18th. After the verification advisory group meeting, the Central Pharmaceutical Affairs Review Committee and the final review committee decide whether to grant CMA through internal and external verification. The MFDS is currently operating the Central Pharmacy Review Committee on matters related to the safety and effectiveness of new drugs in accordance with the Pharmaceutical Affairs Law and is undergoing a procedure to seek advice. Taking into account the severe situation of COVID-19 pandemic, COVID-19 Treatment/Vaccine Safety and Effectiveness Verification Advisory Group and the Final Inspection Committee were additionally formed to go through a triple consultation process. The verification advisory group, the Central Pharmaceutical Affairs Review Committee, and the final review committee are in order. The Verification Advisory Group is a procedure in which the MFDS collects advisory opinions such as clinical, non-clinical, and quality from various experts prior to consulting the Central Pharmaceutical Affairs Review Committee. It was composed of about 30 experts in statistics, etc. Depending on the agenda, an advisory group meeting will be held in which experts in the field participated. The Central Pharmaceutical Affairs Review Committee is an advisory body of the MFDS pursuant to Article 18 of the Pharmaceutical Affairs Law. The advisory committee consists of about 15 members, including standing members of the Biological Drug Subcommittee and related experts, and consults on matters discussed by the verification advisory group and clinical usefulness. The Biologics Subcommittee is a specialized subcommittee for deliberation on the safety and effectiveness of biopharmaceuticals such as vaccines and genetically modified drugs. Prior to the final approval decision, the MFDS plans to hold a'final inspection committee' in which internal and external experts (about 10 people) jointly participate, and conduct a final inspection based on the results of the verification advisory group and the'Central Pharmaceutical Affairs Review Committee . The Ministry of Food and Drug Safety will hold a verification advisory group meeting on the clinical trial data of Celltrion's Rekirona on the 17th, and the results will be released on the 18th. At the verification advisory group meeting, it plans to receive advice on whether the clinical results for the indicators for measuring the clinical effectiveness and the indicators for measuring the principle of operation of the drug used in clinical trial of Rekirona are appropriate to acknowledge the therapeutic effect of this drug. The clinical efficacy measurement index is to evaluate how quickly the administered patient recovers from the seven symptoms of COVID-19 (fever, cough, difficulty breathing, sore throat, muscle pain, fatigue, and headache). A measure of how the drug works is to evaluate how short the time between positive to negative virus test results is reduced. An official from the MFDS said, "We will try to collect various opinions from experts in the process of reviewing the approval of the treatment and vaccine for COVID-19 so that a thorough approval and review can be accomplished.
- Company
- Celltrion's COVID-19 antibody tx reduces progression by 54%
- by An, Kyung-Jin Jan 18, 2021 06:13am
- Rekirona The result of Phase II clinical trial of Rekirona (Regdanvimab), COVID-19 antibody treatment developed by Celltrion, has been revealed for the first time. It is evaluated that it is useful to efficiently manage medical resources while reducing the incidence of severe patients requiring inpatient treatment by more than half and reducing the recovery period. Celltrion presented the results of global II clinical trials related to Rekirona at the 2021 High1 New Drug Development Symposium online event hosted by the pharmaceutical society of Korea on the 13th. This is a multicenter study that compared the efficacy and safety of 327 patients with mild or moderate COVID-19 infection with standard treatment and administration of Rekirona or placebo. 327 COVID-19 patients from Korea, Romania, Spain and the United States participated and completed the final medication on November 25 last year (Korean time). The data introduced on this day are the results of an analysis of 307 mild and moderate patients who were confirmed to be infected with COVID-19 immediately before administration. The presentation was made by Professor Joong Sik Eom (Infectious Internal Medicine, Gachon University Gil Medical Center), chief researcher (PI) and advisor. The researchers set the percentage of patients who died or required hospitalization or oxygen therapy due to COVID-19 infection by the 28th as the efficacy evaluation index. As a result of the analysis, when Rekirona 40mg/kg was administered to patients diagnosed as mild or moderate, the probability of progression to severe was decreased by 54% compared to placebo group. The severe progression rate of moderately ill patients over 50 is 68%. The benefits are expected to increase when Rekirona is administered to patients with higher disease severity in the elderly. The time it takes for the symptoms of COVID-19 to disappear was 5.4 days in Rekirona group, which was shortened by more than 3 days from 8.8 days in the placebo group. In the case of moderate or moderately ill patients over 50 years old, the time it took for symptom recovery after administration of Rekirona was more than 5-6 days with placebo. After administration of Rekirona, the time required for the concentration of virus in the body to decrease by 1500 times was 7 days, which was 3 days shorter than 10 days in the placebo group. No serious adverse events, including death, were reported among the patients participating in the clinical trial. There were no cases of discontinuing the study due to adverse events. Professor Eom said, "When Rekirona is administered to mild or moderate COVID-19 patients, it has been proven to significantly reduce the rate of progression to severe and shorten the recovery time. 56% of the participating patients over 50 years old and those with pneumonia were proven to be an encouraging result in that the participation rate of the high-risk group was high at 60%." Although it is phase II clinical trial, it is expected that it will greatly contribute to the management of medical resources by securing treatment beds to reduce confusion in the treatment field and to provide conditions to focus on moderately high-risk patients. Celltrion officials have completed production for 100,000 people in preparation for conditional marketing authorization of Rekirona. It is planning to conduct phase III clinical trial on a wider range of patients in 10 countries and further verify the safety and efficacy of Rekirona. It plans to conduct phase III clinical trials in more than 10 countries around the world to further verify the safety and efficacy of Rekirona confirmed in phase II clinical trials in a wider range of patients. A Celltrion official said, "We have already completed production for 100,000 people and are thoroughly preparing a supply plan so that we can supply them to the medical field as soon as we acquire CMA." He said, "We are systematically preparing a plan to produce treatments for up to 2 million people so that global supply will not be disrupted in accordance with the timing of approval in major overseas countries."
- Policy
- Will COVID-19 vaccine by SK be released first?
- by Lee, Tak-Sun Jan 15, 2021 06:11am
- Among AstraZeneca's COVID-19 vaccines that have been applied for approval from the MFDS, it is highly likely that the vaccine that SK Bioscience is consigning and producing will be distributed for the first time in Korea. Recently, the MFDS has reported that item approval and lot release can be reviewed in duplicate to speed up the market. The industry analyzes that it will be possible to review vaccines previously produced by SK Bioscience for approval. The health authorities said through a briefing that they are in consultation with AstraZeneca to ensure that the vaccine that is distributed for the first time in Korea will be produced by SK Bioscience. On the 14th, an official from the MFDS said, "There is an exaggerated part of the press report that item approval and lot release are reviewed. Some overlapping periods can occur." Item approval and lot release are different. In the case of vaccines, after item approval, a lot release review is conducted for the products sold in Korea. Therefore, in order for item approval review and national lot release review to overlap, a commercial vaccine must be secured first. The MFDS is required to produce three commercially available lot numbers in advance and submit them as item approval review data according to the regulations on drug safety. Items produced for approval can be used for lot release screening. It is more likely to proceed with lot release for domestically manufactured vaccines rather than imported vaccines that take time due to customs procedures. The MFDS explained in a press release on the 11th that it plans to conduct an on-site survey on SK Bioscience for manufacturing and quality control evaluation during this month. This survey also includes production data for three lots numbers produced in advance. If the GMP (manufacturing and quality control standard) investigation is completed and the feasibility of the clinical trial is secured, it will be possible to review the lot release of commercial vaccines even before approval. The MFDS plans to shorten the period of item approval to a maximum of 40 days (currently more than 180 days) and lot release within a maximum of 20 days (currently 2 to 3 months). In order to start vaccination at the end of February, as announced by the government, lot release must also be carried out during the permit review period. AstraZeneca's COVID-19 vaccine was applied to the MFDS on the 4th. If item approval and lot release are up to 60 days, lot release should also be made during the approval review period. It is said that the health authorities are discussing it, but the vaccine that will be distributed for the first time in Korea is most likely a vaccine produced by SK Bioscience. When asked if the vaccine to be applied for the initial lot release screening is from SK Bioscience, the MFDS responded that it cannot be informed because the item is under review. The imported vaccine that AstraZeneca applied is known to be a product produced in Italy.
- Company
- LG Chem in full throttle seeking anti-obesity and NASH drug
- by An, Kyung-Jin Jan 15, 2021 06:10am
- LG Chem showcased its key new drug pipelines targeting obesity and non-alcoholic steatohepatitis (NASH) at a global event. The South Korean company plans to make the chimeric antigen receptor T (CAR-T) cell therapy and stem cell therapy development into their future growth engine. On Jan. 13, LG Chem announced it would participate in the virtually convened JP Morgan Healthcare Conference 2021 to present the key findings in 40 new drug pipelines. The South Korean company’s session presentation was led by the president of LG Chem Life Sciences Company, Son Jeewoong. At the event, the company addressed the key pipeline such as gout treatment currently undergoing clinical trial, hereditary obesity treatment and NASH treatment. The gout treatment LG Chem is developing as a ‘best in class’ is a new drug that inhibits excessive secretion of uric acid, a major cause of gout. In the Phase I trial in the U.S., the investigational drug was confirmed to effectively lower the uric acid level by only administering once-daily regardless of meal consumption. The drug was evaluated to have verified superior effect and safety compared to existing options as no adverse reaction of hepatotoxicity and cardiovascular system was reported. The company plans to complete the Phase II study in the U.S. in the second quarter and analyze the result. The company’s investigational anti-obesity drug activates an appetite regulating melanocortin-4 receptor gene (MC4R). In last November, an injection with the same mechanism was approved by the U.S. Food and Drug Administration (FDA), but LG Chem’s drug is expected to improve the administration convenience as a first orally taken drug in the class. In September last year, the FDA designated the drug as an orphan drug and granted a market exclusivity benefit to delay a follow-on drug approval for seven years. The investigational NASH drug that prevents expression of vascular adhesion protein 1 (VAP-1) related to liver inflammation and fibrosis currently has an ongoing Phase I clinical trial in the U.S. Its preclinical trial found the drug lessens the risk of drug-drug interaction by being highly selective on the target protein. Considering there is no NASH treatment commercialized worldwide at the moment, LG Chem is speeding up the Phase I clinical trial to complete it in the first quarter of 2022. And at the event, the Korean company also specified the plan to develop a breakthrough anticancer treatment utilizing CAR-T cell and induced pluripotent stem cell (iPSC) therapies. The presenter excitedly expressed the company’s commitment to seek a next-generation stem cell therapy using a treatment-purpose gene. President Son Jeewoong of LG Chem Life Sciences Company noted, “After the merge, the company invested approximately 600 billion won in R&D and drove the open innovation on at all corners to expand our pipeline with 40 candidate medicine. The company would leap as a global bio company with a foundation to continuously release innovative new drug to the market, and also enhance the global new drug competitiveness through constantly conducted clinical trials in the U.S.”
- Policy
- Tamiflu for oral suspension has withdrawn
- by Lee, Tak-Sun Jan 15, 2021 06:10am
- Tamiflu for oral suspension sold overseas In KoreaRoche's original influenza treatment Tamiflu for oral suspension is withdrawn from the domestic market due to the expiration of the product license. Generics for Tamiflu for oral suspension occupied in advance. As of the 13th, the MFDS withdrew Tamiflu for oral suspension 6mg/ml (Oseltamivir) from Roche Korea due to the expiration of the product license. It was approved on January 13, 2016. The main formulation of Tamiflu is capsule type, and patients such as children and the elderly have difficulty swallowing, so the drug in the capsules were ground into powder at a pharmacy and sold for pediatric use. However, since Tamiflu for oral suspension is mixed with water and taken in a liquid form, it is convenient to dispense at a pharmacy, and it is easy for children to take. Roche imported this suspension in Korea and obtained approval for the first time. However, due to the disagreement between Roche headquarters and Roche Korea, it delayed applying for Tamiflu for oral suspension and lost the competition with generic drugs. Hanmi received approval for Hanmi Flu Suspension one month later than Tamiflu for oral suspension, but it was first launched on the market in May 2016 after receiving insurance benefits. Since then, 30 kinds of generic drugs have been launched in 2017. Tamiflu for oral suspension was first approved in Korea, but it missed the timing of its release and started to withdraw from the market. Roche did not even apply for renewal and eventually decided to withdraw the license. Accordingly, Roche is expected to focus more on Tamiflu capsule. It is interpreted that the number of flu patients is decreasing due to the recent COVID-19 epidemic, which also affected the sales of Tamiflu for oral suspension.
- Policy
- Indications for Forxiga include CHF
- by Kim, Jung-Ju Jan 15, 2021 06:10am
- As the indication for AstraZeneca’s SGLT-2 inhibitor Forxiga 10mg (Dapagliflozin) has been extended to chronic heart failure, it is clearly covered in the benefit. On the 12th, the MOHW announced a partial amendment to the 'Pharmaceutical Reimbursement Listing Standard and Method', which establishes the reimbursement standards for additional authorizations for Dapagliflozin. Forxiga 10mg is an SGLT-2 inhibitor administered as an adjunct to diet and exercise therapy to improve blood sugar control in type 2 diabetes patients. The reimbursed price of Forxiga 10mg is ₩784. As of the 22nd of last month, the MFDS expanded the indication to chronic heart failure, requiring management of insurance benefits. Accordingly, the MOHW plans to include it in the notice to clarify the coverage of this indication. The benefits are recognized when Forxiga is administered to type 2 diabetes (general principle). If Forxiga is administered for an indication of chronic heart failure, the patient pays for the drug. The MOHW is planning to inquire industry opinions by the 14th, and it will be implemented and applied from the 15th if there is no specific matter.
- Opinion
- [Reporter's View] Activation of the Generic Substitution
- by Kim, Jung-Ju Jan 14, 2021 01:23pm
- At the beginning of the year, small shops and large companies make actionable plans for the next year. The government plans the budget as well. In addition, the government divides and executes policy projects more detailed and strategically because administrative procedures and processes are more demanding than private enterprises. According to the detailed schedule of the “2021 Comprehensive Health Insurance Plan” released by the MOHW, it is quite encouraging that the government decided to make and finalize an improvement plan within this year for the Incentive system for reducing drug costs for prescription and dispensing. As planned, it is presumed that the consensus was formed by the government, the National Assembly, and the pharmaceutical community to solve the post-notification problem, which has been the biggest issue in the activation of generic substitution, with a computerized system (DUR). However, in more detail, it can be fully assumed that the government is currently facing issues of sustainable health insurance operation and fiscal savings. The government knew that there was a generic substitution activation system as a way to reduce the cost of drugs. Despite the short period of about three months, the results were very meaningful and implications were drawn on the possibility of reducing drug costs. Physicians go through at least two or three selection processes when choosing a drug for prescription. It is the selection of categories, ingredients, and items. Except for the case where the original item is single listed among innovative therapeutic new drugs, the selection of drugs is left to the doctor's medical and subjective judgment. In addition, as the reimbursement standards vary from monotherapy, combination therapy, or three-drug therapy, and there are many generics, the number of cases that can be selected increases. Reduction of drug costs in hospitals can only be achieved by expanding outpatient drug costs. The activation of generic substitution is also directly connected to the problem of financial efficiency management of health insurance and strengthening of coverage in the long term. When the government came up with a comprehensive health insurance plan, it was the same as aiming for a method of investing the amount saved by reinforcement of follow-up management into strengthening coverage. Even if only one side of the hot water balloon is squeezed, the total amount of water never decreases. It is noteworthy that this year's generic substitution system can be activated through the improvement of the incentive system for reducing drug costs for prescription and dispensing.
