New drug research and development is a multi-disciplinary, high-tech, difficult, high investment, long-term, high-risk, high return risk industry. According to statistics, it costs an average of US $500-800 million to launch a new drug in the United States, taking 11-15 years. Patent drugs can monopolize the market and obtain the maximum economic benefits. Among the top 10 drugs in the world, Pfizer has three: Avastin, amlodipine and celecoxib. In 2002, the sales reached US $13.8 billion, and in 2003 alone, the sales of Avastin reached nearly US $9 billion. It can be said that new drug R & D is the locomotive for the development of pharmaceutical industry, and new products are the main source of profit and the driving force for the development of enterprises, which are conducive to the formation of corporate image and brand, and promote the long-term and stable development of enterprises. Therefore, foreign large pharmaceutical enterprises attach great importance to new drug research and development, which accounts for 15% - 20% of their sales.
The sustained growth of China's 1.3 billion population, the demand for medical care, the change of the proportion of population between urban and rural areas, and the aging of population structure have resulted in huge demand for medicine market. Although great achievements have been made in domestic new drug research and development in recent years, there are still problems such as less investment in research and development, weak basic research, low starting point, poor innovation ability, and serious repetition of research and development. In view of the problems and perplexities in the field of new drug research and development in China, the author talks about the strategies and methods of drug research and development based on his own work experience.
Drug research and development is based on the epidemic trend of disease, clinical and market demand, as well as the specific situation of research and development institutions and pharmaceutical enterprises. Generally speaking, there are four strategies and methods of "imitating, following, reforming and creating".
Imitation - that is, to copy the varieties listed in China in accordance with the measures for the administration of drug registration (Trial), mainly including 6 categories of chemical drugs and 9 categories of traditional Chinese medicine.
(1) In recent years, the drugs that have been imitated by the existing national standards have been sold well in China and have changed rapidly in order, and have expired or nearly expired products under domestic protection, including those in short supply in the Pharmacopoeia. The investment in developing such varieties is less (200000-300000 yuan), the cycle is shorter (within 2 years), and the market development cost is lower. For example, amoxicillin, azithromycin, levofloxacin, omeprazole and other varieties of preparations. In 1999, generic drugs accounted for 47.1% of drug sales in the United States and 48% in the United Kingdom,
Germany accounts for 27%. Over the counter (OTC) sales of prescription and over-the-counter drugs in Europe account for about 75:25. China's OTC drug sales increased from 1.91 billion yuan in 1990 and 9.932 billion yuan in 1996 to 20 billion yuan in 2000, and it is expected to reach 60 billion yuan in 2005. There have been imitations and declarations of national standard drugs, from more than 300 in 2001 to more than 4000 varieties in 2003, and there are more than 2000 injection and freeze-dried powder needles alone. The competition will be more intense, so we can't follow blindly.
(2) There are mainly imported drugs instead of domestic ones; more than 30 kinds of anti-tumor drugs have been imported in China, with an import amount of more than 100 million yuan; the import amount of systemic hormone and sensory organ drugs accounts for 50-60% of the total amount of drugs. Most of them have no legal source of raw materials and need to be imitated at the same time. They belong to category 3 + 6 of chemicals, such as imipenem.
Follow up: follow up the drugs or prescriptions listed at home and abroad, including 3 categories of chemicals, 3 + 6 categories of chemicals, and 6 categories of traditional Chinese medicine;
(1) It costs hundreds of millions of dollars to follow up and copy a new drug on the market abroad, with a long cycle (about 10 years) and meticulous research work. At present, it is difficult to achieve the investment cycle and intensity in China. Therefore, it is more realistic to follow up and copy the new drugs (no intellectual property issues in China) and the expired varieties at home and abroad, such as pazufloxacin, bamaxillin, biapenem, etc. There are a large number of generic drugs or over-the-counter drugs with expired patents in foreign countries, which have stable curative effect and good safety. Depending on the situation of patent or administrative protection, it can be imitated, first supplied to the domestic market, and then exported when its patent protection right is lost. The proportion of sales of generic drugs in prescription drugs increased from 10% in 1994 to 20-25% in 2000, which is much higher than the average growth rate of the whole pharmaceutical industry. The average life span of a new drug as a prescription drug is 8 years, and the average life span after it becomes an over-the-counter drug is 34 years. The world OTC drug market increased from US $32.5 billion in 1993 to US $57.1 billion in 1998 and US $65 billion in 2000, with an average annual growth rate of 14%, higher than that of prescription drugs.
(2) Varieties listed at home and abroad with patent protection period, new drug protection period and monitoring period about to expire.
(3) With traditional Chinese medicine through the optimization of traditional Chinese medicine, folk prescription, prescription and ethnic medicine, development of small dose, easy to take, high efficacy of modern dosage forms, or from Chinese medicine extraction and separation and screening of effective ingredients. Traditional Chinese medicine products have important characteristics of OTC drugs and can be an important part of OTC market.
Modification: to change the structure and dosage form of the drugs on the market or change the indications and functions, including 2, 4, 5 categories of chemical drugs, 7, 8 categories of traditional Chinese medicine;
Changing the dosage forms of the drugs on the market, i.e. chemical drugs 5, traditional Chinese medicine 8 and biological drugs 14, the new preparations with special technology can also be monitored for 3 years;
Four kinds of chemical drugs, such as azithromycin, have been changed to be the acid and base of the salt drugs on the market;
To change the way of administration of listed drugs: chemical drugs 5, traditional Chinese medicine 7, biological drugs 12, such as penciclovir;
Change the standard dosage of the drugs on the market -- supplement application 4, cefoperazone 1g → 3G;
Indications or functional indications - supplementary application 3;
There are 8-10 preparations for a API in foreign countries, and only 2-3 preparations in China. China produces more than 1400 kinds of APIs, ranking second in the world in terms of total output, more than 70 kinds of preparations, and more than 3500 varieties and specifications. In the United States, there are 150000 varieties (43 times of China's) and 60000 varieties (17 times of China's) in Germany. There are fewer varieties of antiviral drugs, so the development of preparations is more in-depth. For example, there are 14 kinds of ribavirin and 11 kinds of acyclovir preparations, respectively. The traditional dosage forms (tablets, injections, capsules, etc.) of existing drugs have been developed into sustained-release and controlled-release preparations (sustained-release capsules, sustained-release framework tablets, osmotic pump tablets, controlled-release pellets, controlled-release powders, transdermal controlled-release agents) and targeted preparations (liposomes, microsphere preparations, microcapsules preparations) by applying new technologies, new excipients and new processes, McAb biological missile, receptor targeting drug, etc. are the main approaches and sources of new drug research and development, especially in China, such as compound danshen tablet modified dropping pill, penciclovir modified injection, etc. Cephalosporins and quinolones are concentration dependent anti infectives, which are not suitable for slow and controlled release preparations; too many water needle to freeze-dried powder needle and infusion increase the cost, compatibility problems and security risks.
Creation - new structure, new approach, new compound, etc
(1) Original - a new structure of chemical synthesis or an effective component of natural purification: a new chemical entity, a new molecular object, a new active substance. R & D of innovative drugs with independent intellectual property rights, synthetic drugs such as benflumetol, bicyclol, etc., and purified effective ingredients such as Taxol, Panaxatriol, sodium disuccinate, etc.
(2) Imitations - me too, me better; including improved chemical entities such as docetaxel; soft drugs (active metabolites), such as desloratadine; chiral drugs, such as esomeprazole, l-salbutamol.
(3) Effective parts of traditional Chinese Medicine - 5 categories of traditional Chinese medicine, such as Panax notoginseng saponins.
(4) The new compound preparation, chemical medicine 1.5, is designed with reasonable prescription compatibility to develop the compound of Western medicine or Chinese and Western medicine, so as to reduce the side effects of single medicine, improve the curative effect, prolong the market life of new medicine, and fully meet the different needs of different patients in different situations, such as trivizir (abacavir + lamivudine+ Zidovudine), antihypertensive drugs + blood lipid regulating drugs. The investment cycle and intensity of the new compound preparation are relatively large, and full preparation is required. In order to pursue variety differentiation, blind research and development of compound antibiotics, such as ceftriaxone / tazobactam, pharmacokinetic mismatch between the two, increasing drug resistance opportunities, etc., or simple combination packaging, without research basis for interaction, is not desirable.
In a word, R & D institutions and pharmaceutical enterprises should not only consider disease prevention and control and market, science and technology progress, but also comprehensively consider the scale, development strategy, product characteristics, production conditions and sales mode of enterprises, so as to develop varieties with large clinical value and good market prospects