The world’s leading multinational pharmaceutical company, Sanofi-Aventis France, is dedicated to the research and development of innovative treatment solutions, especially in the field of biomedical research and development. Its diabetes treatment medicines come from anti-coagulant drugs. Races, etc., have become the world's leading biopharmaceuticals. As a leading company in the field of biological medicine, it has a profound understanding of the characteristics of biological drugs. Because of this, it also has unique analysis and insights on the market, development and management of biological generic drugs.
In this article, experts from Sanofi-Aventis pointed out to reporters the development status of the biosimilar market, stating that the characteristics of biopharmaceuticals determine that the market development of biosimilar drugs in the future will not only depend on government needs and expired bio-based organisms. The number of products depends more on the production technology of biosimilars and the government's scientific supervision. At the same time, it is emphasized that it is impossible for different manufacturers to use different production processes to produce truly identical biological products. Therefore, the effectiveness and safety of biosimilar drugs need to be verified through more tests. It cannot be simple. Instead, use the test data of the original product.
The experts in the article introduce the management methods of biosimilars in the United States and Europe, as well as the analysis and suggestions on the management of biosimilars, which are worthy of reference and reference in the industry.
Obvious market demand Biosimilars differ from traditional generics Market development depends on scientific regulation Since 2008, a surge in biopharmaceutical development, investment and attention has emerged in the global pharmaceutical market – not only by patent biopharmaceutical companies This area has expressed concern, and many generic pharmaceutical companies have also shown great interest. However, an expert from Sanofi-Aventis (China) Company (hereinafter referred to as Sanofi) stated in an interview with reporters that in a country or region, the development of biosimilars depends to a large extent on whether Conforms to the characteristics of biosimilars and the level of government supervision.
“The rapid development of the biosimilar market is based on two foundations. First, new biopharmaceuticals continue to be approved; the second is that a large part of the existing biologics patents are about to expire, and by 2016, there will be approximately 25 billion US dollars of biologics. Patent protection will be lost.†Song Zengli, director of pharmaceuticals affairs at Sanofi, told reporters that the global biopharmaceutical industry has undergone two leapfrogging stages: the first stage was the reintroduction of insulin from 1982 to 1997. This stage is mainly a cell. Factor products, these products have entered a period of steady growth from the fast-growing period in the later stages of the first phase of development of the biopharmaceutical industry (1994 to 1997), and as a result, the global biopharmaceutical industry has not been able to sustain its development potential, and its annual sales have remained at a premium. About 100 billion US dollars. After 1997, the biopharmaceutical industry entered a second phase of rapid development as various therapeutic antibodies were successively approved for marketing. The growth rate has remained above 15% for more than 10 years in a row and it has become one of the fastest growing high-tech industries.
The government’s need to reduce the pressure on medical care has also laid the foundation for the development of the biosimilar market. Biopharmaceuticals are mostly used for specialty medicines. Due to the limited market size of specialty drugs, in order to recover development expenditures, the prices of specialty drugs are generally very high. Therefore, only through the development of the biosimilar market can it be possible to greatly reduce the pressure on biomedical products for government medical protection.
Biosimilars are different from the huge capital and time investment in the development of traditional generic drugs. This has led to the launch of generic pharmaceutical products. However, the guidelines issued by the European Medicines Agency (EMEA) Council for Medicinal Products for Human Use on "similar biomedical products" clearly state that similar biopharmaceutical products are not considered to be imitation pharmaceutical products and emphasize that similar studies are required to confirm similarity. In addition to safety and effectiveness, their products must also be fully characterized.
Song Zengli further explained that, unlike conventional generic drugs, because the production process of biopharmaceutical products is very complicated, there are actually no exactly the same biological replicas. Therefore, such imitation products can only be used in certain properties and original research. Drugs are similar and cannot be as safe and equivalent as chemical imitations and original drugs.
“The generic drugs that we usually refer to are generally used to describe generic products of small-molecule chemical drugs that are equivalent in structure and efficacy to original products whose patents have expired or whose data protection has expired. However, this method of evaluation is not It is suitable for the R&D, evaluation and approval of biosimilar drugs.†Song Zengli pointed out that this is because biologics contain relatively large molecules with different characteristics and complexity, and the production process is very complicated, except for the planar primary structure. There are also complex secondary and tertiary spatial structures. It is impossible for different manufacturers to use different production processes to produce truly identical biological products. Therefore, for biosimilars (the more accurate name should be biological analogs), its effectiveness and safety need to be verified through more tests, and it cannot simply be replaced with experimental data of original products. For example, there are more than ten low-molecular-weight heparins used clinically at home and abroad. Because some academic concepts in the field of anticoagulation have not been accurately distinguished, it is generally believed that low-molecular-weight heparin is the same. In fact, due to differences in production processes, chemical structures, etc., there are differences in the clinical efficacy and indications of different low-molecular-weight heparins. Therefore, the World Health Organization (WHO), the United States Food and Drug Administration (FDA) and other institutions have been in several years. It was clearly pointed out before: The characteristics of a low-molecular-weight heparin cannot be arbitrarily extended to another low-molecular-weight heparin. The results of clinical studies targeting a specific low-molecular-weight heparin cannot be generalized to other low-molecular-weight heparins. At the same time, the FDA has already conducted classified management, and according to different manufacturers and sources, low-molecular-weight heparin is divided into different varieties.
Market development depends on scientific supervision. “The characteristics of biopharmaceuticals determine that the market development of biosimilar drugs in the future will not only depend on government needs and the number of expired patented biological products, but also on the production technology level of biosimilars and scientific supervision of the government. "Zhang You, deputy director of registration of Sanofi, said that both the authoritative drug management agency and biopharmaceuticals experts believe that the essential nature of biological products makes it more difficult for biosimilar drug regulatory approval to surpass chemical generic drugs.
In recent years, Europe has established a relatively complete route for the approval of biological analogs and gradually opened the door to biosimilars. EMEA first published guidelines for the evaluation of analogues of biological products in 2005. The guidelines state that biosimilars and biological products that change the production of existing production processes must submit clinical reports and quality reports that demonstrate biocompatibility when they are approved. The guidelines indicate that manufacturers must be able to demonstrate the comparability of quality and safety and efficacy of analogues or process-improved products and reference products (marketed originals). EMEA emphasizes that, in some cases, the comparability of biological analogs cannot be demonstrated. In this case, complete preclinical studies and clinical studies are indispensable.
Although all sectors of the U.S. community expect to see a large number of biosimilars to reduce drug prices, there is currently no formal way to approve biosimilars. In 2007, the U.S. Senate passed a proposal called "Biological Product Price Competition and Innovation Act (BPCIA)" and has delivered it to Congress. If this legislation is passed, the United States is expected to usher in the first biosimilar market in 2011.
Zhang Wenyu, director of pharmaceutical development at Sanofi, frankly stated that there are multi-party games between the original drug companies, generic drug companies, and the government in the future market for biosimilars. Whether related regulatory agencies can well balance the interests of all parties is biosimilar. The key to the smooth development of the future.
Article 12 of the “Administrative Measures for the Registration of Drugs†in China stipulates that generic drugs for biological products shall be registered in accordance with the application procedures for new drugs. According to Annex III of the "Administrative Measures for Drug Registration," all kinds of biosimilar drugs are required to provide pharmaceutical research information such as pharmaceutical research review, formulation prescription, stability study, and comparative data on domestic and foreign marketed products. In this regard, relevant laws and technical guidelines at home and abroad are basically the same, indicating that China's drug regulatory authorities have fully recognized the differences between biosimilar drugs and chemical generic drugs.
In response to the question of how to further improve the management of biosimilar drugs, Zhang Wenyu believes that, first of all, due to the large differences between various varieties of biological products, it is difficult to consider all varieties in an evaluation system, so a separate standard should be established for each variety. Second, since the pre-market evaluation cannot fully demonstrate the safety and effectiveness of biosimilar drugs, long-term and extensive post-market supervision becomes more important. For example, the EMEA guidelines require manufacturers to include post-market surveillance plans in their product filings and require listed drugs to be tested at least once a year after listing. Thirdly, the current domestic product standards for biological products are relatively simple. Compared with the international prevailing standards and foreign enterprise standards, the indicators of content and purity are relatively low, which is very unfavorable to the comprehensive control of product quality. Therefore, the quality standards for biosimilar drugs should be further improved, especially the improvement of product purity and quality control of finished products. Fourth, because the characteristics of biological products will be affected by any simple operation in the production process, more emphasis must be placed on process supervision so that the parameters of each step of the intermediate product are under strict monitoring and can enable producers and regulators to learn The effect of important process parameters on the characteristics of the final product. Finally, due to the worldwide lack of clinical experience with biosimilars, it is the responsibility of all countries to actively establish and improve the clinical database of biosimilars and improve the safety and effectiveness of clinical use.
Related links The State Food and Drug Administration changed the generic name of anticoagulant drug Kesai from "low molecular heparin sodium" to "enoxaparin sodium" based on "different clinical efficacy and indications of low molecular weight heparin are different." For this reason. The unique production process of enoxaparin sodium makes its chemical structure, the average molecular weight of the compound, the combination of antithrombin III and HCII, anti-Xa/anti-IIa ratio, and the like unique. Since the unique manufacturing process determines the irreproducibility of the efficacy characteristics and safety of enoxaparin sodium, the ACC/AHA guidelines clearly emphasizes that only the recommended low molecular weight heparin is enoxaparin rather than generically low molecular heparin; A change of name is also intended to be in line with international standards, because the use of "enoxaparin sodium" as the common name of Kesai in the world.
The consensus of the European Council, the U.S. Food and Drug Administration, and the U.S. and European Society of Cardiology and other authoritative bodies is that different biological products are not interchangeable. This suggests that when clinically selecting drugs, it should be borne in mind that they cannot be regarded as having the same molecular weight, anti-factor Xa or anti-factor IIa activity, and/or anti-Xa/anti-IIa ratio as the enoxaparin, and are considered to be identical. The pharmacological activity, the same efficacy and safety.
Similarly, the State Food and Drug Administration has designated the general name of domestically produced long-acting insulin as “recombinant insulin glargineâ€, which is distinguished from the common name “Glargin Insulinâ€, which is based on the Pharmacological activity, curative effect, and the two products. There is a difference in security. The complex structure and sensitivity of insulin and its analogues, cumbersome production processes and quality control determine the non-reproducibility of insulin and its analogues.
In this article, experts from Sanofi-Aventis pointed out to reporters the development status of the biosimilar market, stating that the characteristics of biopharmaceuticals determine that the market development of biosimilar drugs in the future will not only depend on government needs and expired bio-based organisms. The number of products depends more on the production technology of biosimilars and the government's scientific supervision. At the same time, it is emphasized that it is impossible for different manufacturers to use different production processes to produce truly identical biological products. Therefore, the effectiveness and safety of biosimilar drugs need to be verified through more tests. It cannot be simple. Instead, use the test data of the original product.
The experts in the article introduce the management methods of biosimilars in the United States and Europe, as well as the analysis and suggestions on the management of biosimilars, which are worthy of reference and reference in the industry.
Obvious market demand Biosimilars differ from traditional generics Market development depends on scientific regulation Since 2008, a surge in biopharmaceutical development, investment and attention has emerged in the global pharmaceutical market – not only by patent biopharmaceutical companies This area has expressed concern, and many generic pharmaceutical companies have also shown great interest. However, an expert from Sanofi-Aventis (China) Company (hereinafter referred to as Sanofi) stated in an interview with reporters that in a country or region, the development of biosimilars depends to a large extent on whether Conforms to the characteristics of biosimilars and the level of government supervision.
“The rapid development of the biosimilar market is based on two foundations. First, new biopharmaceuticals continue to be approved; the second is that a large part of the existing biologics patents are about to expire, and by 2016, there will be approximately 25 billion US dollars of biologics. Patent protection will be lost.†Song Zengli, director of pharmaceuticals affairs at Sanofi, told reporters that the global biopharmaceutical industry has undergone two leapfrogging stages: the first stage was the reintroduction of insulin from 1982 to 1997. This stage is mainly a cell. Factor products, these products have entered a period of steady growth from the fast-growing period in the later stages of the first phase of development of the biopharmaceutical industry (1994 to 1997), and as a result, the global biopharmaceutical industry has not been able to sustain its development potential, and its annual sales have remained at a premium. About 100 billion US dollars. After 1997, the biopharmaceutical industry entered a second phase of rapid development as various therapeutic antibodies were successively approved for marketing. The growth rate has remained above 15% for more than 10 years in a row and it has become one of the fastest growing high-tech industries.
The government’s need to reduce the pressure on medical care has also laid the foundation for the development of the biosimilar market. Biopharmaceuticals are mostly used for specialty medicines. Due to the limited market size of specialty drugs, in order to recover development expenditures, the prices of specialty drugs are generally very high. Therefore, only through the development of the biosimilar market can it be possible to greatly reduce the pressure on biomedical products for government medical protection.
Biosimilars are different from the huge capital and time investment in the development of traditional generic drugs. This has led to the launch of generic pharmaceutical products. However, the guidelines issued by the European Medicines Agency (EMEA) Council for Medicinal Products for Human Use on "similar biomedical products" clearly state that similar biopharmaceutical products are not considered to be imitation pharmaceutical products and emphasize that similar studies are required to confirm similarity. In addition to safety and effectiveness, their products must also be fully characterized.
Song Zengli further explained that, unlike conventional generic drugs, because the production process of biopharmaceutical products is very complicated, there are actually no exactly the same biological replicas. Therefore, such imitation products can only be used in certain properties and original research. Drugs are similar and cannot be as safe and equivalent as chemical imitations and original drugs.
“The generic drugs that we usually refer to are generally used to describe generic products of small-molecule chemical drugs that are equivalent in structure and efficacy to original products whose patents have expired or whose data protection has expired. However, this method of evaluation is not It is suitable for the R&D, evaluation and approval of biosimilar drugs.†Song Zengli pointed out that this is because biologics contain relatively large molecules with different characteristics and complexity, and the production process is very complicated, except for the planar primary structure. There are also complex secondary and tertiary spatial structures. It is impossible for different manufacturers to use different production processes to produce truly identical biological products. Therefore, for biosimilars (the more accurate name should be biological analogs), its effectiveness and safety need to be verified through more tests, and it cannot simply be replaced with experimental data of original products. For example, there are more than ten low-molecular-weight heparins used clinically at home and abroad. Because some academic concepts in the field of anticoagulation have not been accurately distinguished, it is generally believed that low-molecular-weight heparin is the same. In fact, due to differences in production processes, chemical structures, etc., there are differences in the clinical efficacy and indications of different low-molecular-weight heparins. Therefore, the World Health Organization (WHO), the United States Food and Drug Administration (FDA) and other institutions have been in several years. It was clearly pointed out before: The characteristics of a low-molecular-weight heparin cannot be arbitrarily extended to another low-molecular-weight heparin. The results of clinical studies targeting a specific low-molecular-weight heparin cannot be generalized to other low-molecular-weight heparins. At the same time, the FDA has already conducted classified management, and according to different manufacturers and sources, low-molecular-weight heparin is divided into different varieties.
Market development depends on scientific supervision. “The characteristics of biopharmaceuticals determine that the market development of biosimilar drugs in the future will not only depend on government needs and the number of expired patented biological products, but also on the production technology level of biosimilars and scientific supervision of the government. "Zhang You, deputy director of registration of Sanofi, said that both the authoritative drug management agency and biopharmaceuticals experts believe that the essential nature of biological products makes it more difficult for biosimilar drug regulatory approval to surpass chemical generic drugs.
In recent years, Europe has established a relatively complete route for the approval of biological analogs and gradually opened the door to biosimilars. EMEA first published guidelines for the evaluation of analogues of biological products in 2005. The guidelines state that biosimilars and biological products that change the production of existing production processes must submit clinical reports and quality reports that demonstrate biocompatibility when they are approved. The guidelines indicate that manufacturers must be able to demonstrate the comparability of quality and safety and efficacy of analogues or process-improved products and reference products (marketed originals). EMEA emphasizes that, in some cases, the comparability of biological analogs cannot be demonstrated. In this case, complete preclinical studies and clinical studies are indispensable.
Although all sectors of the U.S. community expect to see a large number of biosimilars to reduce drug prices, there is currently no formal way to approve biosimilars. In 2007, the U.S. Senate passed a proposal called "Biological Product Price Competition and Innovation Act (BPCIA)" and has delivered it to Congress. If this legislation is passed, the United States is expected to usher in the first biosimilar market in 2011.
Zhang Wenyu, director of pharmaceutical development at Sanofi, frankly stated that there are multi-party games between the original drug companies, generic drug companies, and the government in the future market for biosimilars. Whether related regulatory agencies can well balance the interests of all parties is biosimilar. The key to the smooth development of the future.
Article 12 of the “Administrative Measures for the Registration of Drugs†in China stipulates that generic drugs for biological products shall be registered in accordance with the application procedures for new drugs. According to Annex III of the "Administrative Measures for Drug Registration," all kinds of biosimilar drugs are required to provide pharmaceutical research information such as pharmaceutical research review, formulation prescription, stability study, and comparative data on domestic and foreign marketed products. In this regard, relevant laws and technical guidelines at home and abroad are basically the same, indicating that China's drug regulatory authorities have fully recognized the differences between biosimilar drugs and chemical generic drugs.
In response to the question of how to further improve the management of biosimilar drugs, Zhang Wenyu believes that, first of all, due to the large differences between various varieties of biological products, it is difficult to consider all varieties in an evaluation system, so a separate standard should be established for each variety. Second, since the pre-market evaluation cannot fully demonstrate the safety and effectiveness of biosimilar drugs, long-term and extensive post-market supervision becomes more important. For example, the EMEA guidelines require manufacturers to include post-market surveillance plans in their product filings and require listed drugs to be tested at least once a year after listing. Thirdly, the current domestic product standards for biological products are relatively simple. Compared with the international prevailing standards and foreign enterprise standards, the indicators of content and purity are relatively low, which is very unfavorable to the comprehensive control of product quality. Therefore, the quality standards for biosimilar drugs should be further improved, especially the improvement of product purity and quality control of finished products. Fourth, because the characteristics of biological products will be affected by any simple operation in the production process, more emphasis must be placed on process supervision so that the parameters of each step of the intermediate product are under strict monitoring and can enable producers and regulators to learn The effect of important process parameters on the characteristics of the final product. Finally, due to the worldwide lack of clinical experience with biosimilars, it is the responsibility of all countries to actively establish and improve the clinical database of biosimilars and improve the safety and effectiveness of clinical use.
Related links The State Food and Drug Administration changed the generic name of anticoagulant drug Kesai from "low molecular heparin sodium" to "enoxaparin sodium" based on "different clinical efficacy and indications of low molecular weight heparin are different." For this reason. The unique production process of enoxaparin sodium makes its chemical structure, the average molecular weight of the compound, the combination of antithrombin III and HCII, anti-Xa/anti-IIa ratio, and the like unique. Since the unique manufacturing process determines the irreproducibility of the efficacy characteristics and safety of enoxaparin sodium, the ACC/AHA guidelines clearly emphasizes that only the recommended low molecular weight heparin is enoxaparin rather than generically low molecular heparin; A change of name is also intended to be in line with international standards, because the use of "enoxaparin sodium" as the common name of Kesai in the world.
The consensus of the European Council, the U.S. Food and Drug Administration, and the U.S. and European Society of Cardiology and other authoritative bodies is that different biological products are not interchangeable. This suggests that when clinically selecting drugs, it should be borne in mind that they cannot be regarded as having the same molecular weight, anti-factor Xa or anti-factor IIa activity, and/or anti-Xa/anti-IIa ratio as the enoxaparin, and are considered to be identical. The pharmacological activity, the same efficacy and safety.
Similarly, the State Food and Drug Administration has designated the general name of domestically produced long-acting insulin as “recombinant insulin glargineâ€, which is distinguished from the common name “Glargin Insulinâ€, which is based on the Pharmacological activity, curative effect, and the two products. There is a difference in security. The complex structure and sensitivity of insulin and its analogues, cumbersome production processes and quality control determine the non-reproducibility of insulin and its analogues.
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