guide

The pharmaceutical industry began in the middle of the19th century, and entered the core of medical care from the edge, becoming a global industrial industry. The pharmaceutical industry has gained a prominent position today. On the one hand, the government supports the research and development of drugs to prolong human life, improve the quality of human life and prevent diseases; At the same time, it also strengthened supervision, including its safety and effectiveness. The government should also take measures to quell people's complaints that pharmaceutical companies get high returns through new drug products and promotion. The reform of the medical system is being carried out worldwide.

The challenge facing the pharmaceutical industry is the complex interaction and influence among scientists, industry, relevant government departments, doctors and patients in the process of new drugs moving from laboratory to practical use.

As a government examination and approval department, it is also a dilemma. If it is not approved, many people's efforts will be in vain. If approved, it may bring a series of adverse reactions and even lawsuits after listing. The recent COX-2 inhibitor incident and the adverse reaction of antidepressants to suicide are good examples. It is not easy for FDA staff to review nearly 50 thousand pages of registration materials.

The pharmaceutical industry is facing the same difficulties. Investors need early return on investment and high return on investment. They want pharmaceutical companies to develop and sell so-called "blockbuster" drugs. But in fact, drug research and development is becoming more and more difficult, and new drugs often have no products. With the cautious attitude of FDA and other drug regulatory authorities and patients' conscious awareness of adverse reactions, patients' reactions to pharmaceutical companies' research and development of preventive drugs such as AIDS and malaria are incurable and expensive. Harris

Poll Consulting's recent public opinion survey found that people's satisfaction with pharmaceutical companies dropped from 79% in 1997 to 44% in 2004, a significant drop of 35%. In fact, the support rate of patients and consumers in China for pharmaceutical companies and the health care industry, including the health sector, may also be declining. Just lack of statistics. This may be the contradiction between the public's moral standards and the profit maximization of pharmaceutical companies as enterprises.

1870- 1930

At this stage, early pharmacists began to mass-produce drugs commonly used at that time in the laboratory, such as morphine, quinine, brucine and so on. At the same time, in 1880, dye enterprises and chemical plants at that time began to establish laboratories to research and develop new drugs. Merck Pharmaceuticals, for example, started as a small pharmacy in darmstadt in 1668, and began to wholesale medicines in1840s. From1830s to1890s, similar enterprises developed from pharmacies to large-scale manufacturers of drugs, including Schilling Pharmaceutical Company in Germany, Hoffman-Roche Pharmaceutical Company in Switzerland and Wellcome Pharmaceutical Company in Britain (Burroughs

Weikang), Etienne of France

Plain Pharmaceutical Company, Abbott Pharmaceutical Company, SmithKline Pharmaceutical Company, Lilly Pharmaceutical Company, Puqiang Pharmaceutical Company and Parker-Davis Company, etc. Some pharmaceutical companies today used to be chemical plants and dye factories, such as Akfa, Bayer and Hearst in Germany. Ciba Pharmaceutical Company, Jiaji Pharmaceutical Company and Shandaoshi Pharmaceutical Company in Switzerland; Bremen in Britain and Pfizer in the United States. At the end of 19, these enterprises began to merge into real pharmaceutical enterprises, and their scientific basis was medicinal chemistry and pharmacology. The application of synthetic chemistry and pharmacology, especially the study of indications of compounds, has made the pharmaceutical industry develop by leaps and bounds.

The pharmaceutical industry should be said to have started in Germany, and now the United States and Britain are leading. At the end of 19, some dye industries and chemical industries merged into pharmaceutical industries, and some scientists began to study the structure-activity theory of drugs. The research direction of new pharmaceutical enterprises is to identify and prepare synthetic drugs and study their therapeutic effects. Pharmaceutical companies began to cooperate with academia in Germany, just as they are now in Europe and America. At that time, dyes, immune antibodies and other physiologically active substances were used to understand their effects on pathogenic bacteria. 1906 Paul.

Ehrlich discovered that some synthetic compounds can selectively kill parasites, germs and other pathogenic bacteria, which triggered large-scale industrial research and continues to this day. /kloc-At the beginning of the 9th century, chemists have been able to extract and concentrate effective components from plants for therapeutic purposes. Effective components such as morphine, quinine and adrenaline can also be extracted from animals in a similar way at the beginning of the 20th century. It should be said that this is the first hormone used for therapeutic purposes. At that time, people had learned to extract dyes from cola and kill bacteria through dyeing, which can be confirmed by microscopic observation. Chemists quickly improved the structure of these dyes, including their by-products, to make new compounds more effective. Synthetic chemistry developed rapidly at this time. Many products are still widely used, such as paracetamol (paracetamol) used in Tylenol, Baifuning and Baijiahei, which is the active metabolite of N- acetanilide and phenacetin. Another example is Felix, a chemist from Bayer Company.

Hoffman synthesized aspirin from salicylic acid, and aspirin is still one of the most productive drugs. /kloc-vaccines, including BCG vaccine and diphtheria vaccine, were also used in the late 20th century.

At the beginning of the structure-activity theory research, animals and people were used to do vaccine, antitoxin and antibody experiments, and the chemical knowledge at that time and the molecular structure knowledge of dyes were used in the experiments. The structure-activity relationship theory enabled ehrlich to synthesize the syphilis drug Salvarsan, which is considered to be the first drug synthesized by a systematic method.

From 65438 to 0909, the American Chemical Society established a branch of medicinal chemistry, which reflected the importance attached by the pharmaceutical industry to chemists and chemical science at that time. 1906 promulgated by the US Food and Drug Law also urges pharmaceutical companies to hire more chemists to accurately analyze drugs. At that time, American chemists were not free to synthesize new compounds, and pharmaceutical companies only produced simple compound drugs. German chemists are in a monopoly. World War I prevented German technology from reaching the United States, prompting the United States to attach importance to its own development and production of aspirin, Softhom, Verona and other drugs, which can be used to treat the pain of the wounded in the war. 1920, the branch was renamed as pharmaceutical branch, 1927, and it was renamed as pharmaceutical branch, which is still in use today.

In the past, prescriptions could be patented, but in fact, prescriptions could not be protected because the instructions and labels required descriptions of prescription ingredients. According to the regulations, the drug supervision department has the right to require products to withdraw from the market and advertising restrictions.

Before 1930, most drugs were sold without prescription, half of which were prepared by pharmacists, and sometimes doctors wrote prescriptions for patients themselves. Pharmaceutical companies also provide some prescription drugs commonly used by doctors, and the prescriptions are provided by doctors. China has been like this for a long time. Because of the strength of doctors in Europe and America at that time, pharmaceutical factories only produced some general drugs, such as drugs for treating pain, infection and heart disease. Although it is very encouraging to treat diseases with drugs obtained from chemical synthesis research, only a small amount of compounds, such as vitamins and insulin, were used at that time. The development of medicinal chemistry develops with the development of medicine and drug market.

The 1930s and 1960s were the golden ages of pharmaceutical industry.

The 1930s and 1960s were the golden age of pharmaceutical industry because a large number of drugs were invented during this period, including synthetic vitamins, sulfonamides, antibiotics and hormones (thyroxine, oxytocin and cortisone). ), antipsychotics, antihistamines and new vaccines. Many of them are brand-new drugs. During this period, the infant mortality rate dropped by 50%.

In fact, the number of children who died of infection dropped by 90%. Many diseases that could not be treated in the past, such as tuberculosis, diphtheria and pneumonia, can be cured, which is also the first time in human history.

Of course, on the other hand, the war has also accelerated the research and development of drugs, and some war-related projects have been funded by the government, such as antimalarial drug treatment, cortisone (which can make people on the plane not temporarily dizzy at high altitude), especially penicillin. 1 1 American pharmaceutical companies participated in the development of penicillin, which was directly led by the wartime production department. After World War II, the United States became the leader of the world pharmaceutical industry. By the end of1940s, the United States produced almost half of the world's drugs, accounting for 1/3 of the international drug trade.

Due to the increase in drug research and development and market investment, pharmaceutical companies in the United States, Europe and Japan are growing rapidly. Cooperation between R&D and academia has also been strengthened. The method of drug invention has also changed greatly. For example, in the development of antibiotics, pharmaceutical factories screened thousands of soil samples to find antibacterial agents. Typical compounds in this period are: streptomycin of Merck, chlortetracycline of Rieter, chloramphenicol of Peida, erythromycin of Abbott and Lilly, tetracycline of Pfizer, etc. The profit return of these pharmaceutical markets has prompted pharmaceutical companies to pay more attention to scientific research and start to establish special scientific research parks.

The characteristic of this period is that pharmaceutical enterprises have studied natural substances, discovered new drugs, transformed natural substances, synthesized new compounds by synthetic chemistry, and obtained new drugs by screening compounds. Along with this course, analytical chemistry and instrumental analysis technology have also made great progress, because it is necessary to determine the chemical structures of compounds, steroid hormones and antibiotics. Including X-ray diffraction technology, ultraviolet spectrum technology and infrared spectrum technology, from the wet chemistry era using flasks and test tubes to the dry chemistry era using trace samples and molecular models. The development of these technologies enables chemists to explain the structure-activity theory more scientifically and understand the relationship between chemical structure and biological activity. This has led to the emergence of a new generation of antipsychotics, sleeping pills, antidepressants and antihistamines.

During this period, drug safety was concerned. The sulfanilamide drugs in 1937 caused more than one death in 100, most of them were children, which made the US Drug Administration aware of the lack of drug safety regulations. At that time, scientists from S.E.Massengill Company prepared sulfanilamide syrup with slightly sweet diethanol. Although there are indicators such as appearance, taste and smell in the standard, there is no animal test and no comparison with published solvent literature, which leads to tragedy. This also quickly contributed to the adoption of 1938 Food, Drug and Cosmetic Law. The main revision is the responsibility of the drug supervision department to approve new drugs. Require officials to review preclinical trial data and clinical trial data, have the right to require applicants to increase trial items, and have the right to refuse to approve the listing.

At that time, the United States was more advanced in drug safety in the world, because Germany, as a defeated country, still imposed a wartime ban on new drugs in the 1960s and 1950s, while Britain did not have a drug law (TSA) until 1956, so the government paid more attention to drug management, such as standards for testing and production. The introduction of OTC regulations makes it easier for patients to obtain general therapeutic drugs, that is, self-treatment drugs, but it also increases the profits of prescription drugs. The so-called "R&D pharmaceutical companies" have gradually emerged.

In clinical trials, both sides are required to conduct controlled trials. Because clinical trial data are needed, the scope of drug use is controlled and drug abuse is prevented. Although western countries have not solved the problem of drug abuse so far, the number of drug addicts in the United States has reached tens of millions every year.

Although government departments have strengthened drug safety supervision, in fact, the responsibility for drug clinical trials is still borne by pharmaceutical companies, not the government or the third party. Clinical trial data enables pharmaceutical companies to understand the target audience of the market, which is conducive to drug sales. Because the target audience of pharmaceutical companies is not patients, but doctors, doctors prescribe drugs, pharmacies distribute drugs, and patients are still blindly using drugs. world

This is the case in all countries. Recently, Washington Post said that there are 1565438+ 10,000 people who abuse drugs in the United States, and 4% of doctors have no training in drugs.

For a period of time after World War II, the idea of European Social Democratic Party made the idea of European welfare state deeply rooted in people's hearts, and medical care became a kind of welfare, while the United States implemented a medical insurance system, which made people indifferent to drug prices, including doctors and patients.

Reassessment, Regulation Revision and Growth of Pharmaceutical Industry (1960- 1980)

In fact, the most important thing in this period is the publication of GMP for drug production, which brings verification into the requirements of GMP regulations and makes drug production more standardized.

During this period, the pharmaceutical industry was impacted by science, medicine, politics, market and other aspects. The discovery of new compounds and early experiments made a batch of new products come out, which made it possible to selectively block physiological processes and treat diseases. Especially in cardiovascular drugs, β -blockers represented by Naylor appeared in 1960s, ACE inhibitors represented by captopril in 1970s and 1980s, calcium antagonists represented by nifedipine, and some lipid-lowering drugs. Antidepressants and antihistamines with less adverse reactions; Non-steroidal antipyretic and analgesic drugs represented by ibuprofen; Oral contraceptives; Anticancer drugs; Drugs for treating Parkinson's disease represented by dopamine; Drugs for asthma, etc. The FDA of the United States has strengthened the management of clinical trials, while compared with the United States, the European government has a loose management of drug clinical trials, requiring doctors to supervise the adverse reactions of patients after taking drugs. Therefore, the speed of listing new drugs in Europe is faster than that in the United States, but the situation of adverse drug reactions in Europe is also more serious than that in the United States. If thalidomide is not approved by FDA, there will be no serious adverse reactions in the United States. In this case, American pharmaceutical companies began to diversify, such as getting involved in consumer goods industries such as spices and cosmetics.

During this period, the theoretical design in science (rationality

Design) has been developed, because the knowledge of receptors and substrates of enzymes, hormones and neurotransmitters related to certain diseases has become the basic knowledge for studying the biochemical and physiological processes of human body; At the same time, scientific discoveries also involve blocking the function of target molecules. The study of natural resources includes substances with biochemical functions produced by microorganisms. The change of molecular structure, that is, the synthesis of so-called me-too compounds, became the characteristic of this period. The typical modification of molecular structure is captopril, and the typical metabolite is terfenadine, an antihistamine.

Breakthroughs in instrumental analysis in the era of 1960- 1970 included nuclear magnetic resonance spectroscopy and high performance liquid chromatography, which also made great contributions to drug invention. The invention of computers has also made complex calculations simple. Such as the calculation of Fourier transform. The establishment of the database also enables the data of production, clinical trials, analysis and other reference materials to be stored, and the results can be compared and analyzed.

Because of the use of new instruments and computers, the drug administration has also formulated corresponding laws and regulations.

During this period, drug prices have also been put on the agenda, because there is a big gap between the prices of raw materials and finished drugs. This proposal was put forward by Senator estes.

Kefauver proposed it. Almost at the same time, thalidomide was reported in Europe 196 1, and there were about 10000 cases of teratoma in the world, including Europe, South America and Asia. This product is produced by Gruenenthal Pharmaceutical Factory in Germany. Although the Federal Measures for New Drug Approval was revised in 19 1, the final German regulations were not implemented until 1976, which strengthened the control over the safety and effectiveness of new drugs. In response to a similar crisis in Britain, the Ministry of Health set up the Drug Safety Committee (CSD) in 1963. It works closely with the government, but it is not a legislative body. It does not supervise the behavior of doctors and the pharmaceutical industry before and during clinical trials. 1968, it is stipulated to be controlled by the drug safety Committee.

New drug products enter the market.

Although thalidomide did not harm the United States, Kefufu and others put forward a proposal, asking Congress to study and pass new laws and regulations, cross-approve drug patents, limit drug prices, and promote drugs. , in order to reduce the price of drugs; Regulations should also cover the standards of drug safety and effectiveness. 1962, Congress passed the Kefauver-Harris Supplementary Regulations of the Food, Drug and Cosmetics Act of the FDA. It is required to evaluate the use of drugs by quantitative methods, and FDA can postpone or disapprove the application of NDA new drugs through new regulations. Therefore, pharmaceutical companies have invested a lot of money in preclinical trials and clinical trials. The number of experimental cases has increased from the original 10-100 to more than one thousand. At this time, large pharmaceutical companies complain that the number of new drugs on the market is rapidly decreasing. Some pharmaceutical companies have shifted their business fields to medical devices, diagnostic reagents, optical instruments, cosmetics, food, and even household necessities. American pharmaceutical companies began to strengthen overseas drug sales and international scientific research cooperation, such as cooperation with Europe, South America and Asia.

Market competition, enterprise merger, biotechnology and other high-tech periods, 1980- now.

In the past 20 years, the pharmaceutical industry has introduced a series of new products to the market, including central nervous system drugs, anti-virus and retrovirus infection drugs (especially drugs for treating HIV and AIDS), and drugs for treating cancer. During this period, biotechnology has been greatly developed, such as interferon, white blood cells, erythropoietin, monoclonal antibody drugs and so on. Can simulate or support the human immune system. Insulin extracted from animals in the past can be used for transgenic microorganisms.

There are many new methods in scientific research, such as computer chemistry, combinatorial chemistry, and rapid screening of compounds by biotechnology, which have changed the traditional drug research. Many pharmaceutical companies have their own compound databases. Because new drugs are difficult to predict, the government also controls the entry into the pharmaceutical industry through laws and regulations, and there are few new pharmaceutical companies. As a new technology, biotechnology has become an indispensable part of the pharmaceutical industry. They are committed to combining new technologies such as biology, Genentech and genomics. According to recent statistics, more than 30% of the new drugs listed in recent years are biotechnological products, and 50% of the new drug projects under development are biotechnological products. Moreover, after the trough of the new economic tide from 65438 to 0999-2002, biotechnology enterprises reshuffled, and some biotechnology enterprises became new giants, such as Amgen. The United States is still in a leading position in the field of biotechnology, and Europe is planning to increase investment in research and development. Some European companies have established joint ventures with American pharmaceutical companies or set up R&D institutions in North America. Although there are many means to develop new drugs, it still depends on luck to a large extent, so it can be said that the production of new products is a combination of theoretical research and luck, and it has not changed today.

The discovery of many compounds is to synthesize a series of potentially useful compounds first, and then quickly screen them, such as physical analysis and biological analysis methods. In order to quickly analyze the metabolic process in the body, whether it binds to the subject matter and reacts, toxic reactions, etc. In this regard, pharmaceutical companies have invested a lot of money, but its efficacy is still controversial.

Another great discovery is that genetic engineers have been able to prepare target microorganisms through DNA recombination, which can produce the required compound molecules. This method has been widely used. The future development direction may include gene repair with engineering cells.

In terms of policy, 1980, the US High Court ruled that microorganisms obtained through genetic technology can apply for patents; Congress passed the Bayh-Dole Act, allowing beneficiaries funded by federal funds to obtain patent protection; At the same time, biotechnology enterprises are allowed to raise funds. A typical example is Genentech, the first listed biotechnology company, whose stock soared from $35 to 89 yuan within two minutes of listing, which shows the market's expectations for biotechnology companies at that time.

During this period, thousands of biotechnology enterprises obtained financing, including listing and venture capital. Unprecedented phenomena in history include lifelong scientists entering the board of directors, investors believing in the future sales and profits promised by biotechnology companies, and some untested compounds applying for patents. Biotechnology companies claim that their products can treat diseases such as cancer, diabetes and AIDS that cannot be treated by current technology. Biotechnology enterprises closed down and new ones were born. Today in 2005, there are still 65,438+0,500 biotechnology enterprises in the United States.

Europe is still relatively conservative in this respect. Biotechnology enterprises were mainly born in1mid-1990s. So far, Europe still lags behind the United States, but it is working hard.

Another feature of this period is that since 2000, many so-called heavy product patents have expired, and generic drug companies have begun to take the opportunity to develop, including multinational pharmaceutical companies, such as Novartis Pharmaceutical Company, which are acquiring generic drug companies on a large scale; Including Indian pharmaceutical companies, have gone global, although the road is not smooth. In 2005-2008, there will be another $35 billion in the trademark market due to the expiration of patents. In 2004, there were 10375 medical products in American orange book, of which 7602 were generic drugs.

This period is also the era of enterprise merger. 1994, American household products company joined Wyeth pharmaceutical company. 1995 GlaxoSmithKline acquired Wellcome Pharmaceutical Company, and Famaxia Pharmaceutical Company and Puqiang Pharmaceutical Company merged; Novartis Pharmaceutical Company was founded in 1996, and was originally Ciba Pharmaceutical Company and Shandaoshi Pharmaceutical Company; 1999 Established Aventis Pharmaceutical Company, which consists of Hearst Pharmaceutical Company and Ronaplan Pharmaceutical Company; In 2000, Pfizer acquired Vanalan Baxter Pharmaceutical Company, and in 2003, it acquired Famacia Pharmaceutical Company. In 2004, Aventis and Sanofi merged. The market share of the top 10 pharmaceutical companies in the world has reached 47%, while Pfizer is close to 10%. Explain the monopoly of the pharmaceutical industry. However, large enterprises are also facing enormous challenges. Perhaps the golden age of traditional pharmaceutical companies will never come again.

The future of pharmaceutical industry

Pharmaceutical enterprises and biotechnology enterprises will strengthen cooperation and mergers and acquisitions.

There will still be conflicts between social benefits and corporate interests, and the government will coordinate these issues. Including drug price control, encouraging the use of generic drugs, strengthening the supervision of adverse drug reactions, and preventing drug abuse. The reform of the medical system will continue.

Biotechnology enterprises have gradually matured, and some biotechnology enterprises have the ability of self-financing. In the future, some biotechnology companies will compete with multinational pharmaceutical companies on the same starting line.

Pharmaceutical enterprises will become more specialized and devote themselves to specialized treatment fields or indications.

The difficulty of research and development will increase, and the reliability and accuracy of clinical trials are particularly important, otherwise it will encounter litigation. The compliance of GMP and financial management will be valued by enterprises, and the management departments such as FDA, EMEA and SEC will strengthen supervision and management, and the punishment will also increase.