I have heard several interesting sayings about domestic drugs, all of which were said by doctors. One said that cardiovascular drugs can be eaten domestically in summer, and the risk factor is relatively high in winter, so you must take imported drugs. Another said that you can take imported drugs when you first get sick, and you can switch to domestic drugs when your condition is stable. Another doctor said that ordinary patients have limited medical insurance coverage and can only take domestic medicines. The amount of medical insurance for veteran cadres is much higher, and it is almost uncapped, so all the cadre wards in our hospital use imported drugs.
Practitioners in the pharmaceutical industry have different views. They generally think that the quality of domestic drugs is ok, especially those produced in recent years, and the quality should be good. However, they also admit that there are indeed some domestic drugs with poor quality. These black sheep make doctors and patients distrust domestic drugs, and as a result, their industries are collectively accused.
Of course, it is understandable for the pharmaceutical industry to speak for itself. What is the quality of domestic drugs? Let's clarify a few definitions first. When I say domestic drugs here, I mean solid tablets. I don't discuss injection or biological agents, but only oral tablets and capsules. These two drugs account for the bulk of the pharmaceutical market, and their core components are small molecular compounds. In addition, Chinese medicine does not discuss it, and there is basically no difference between domestic and imported.
Here, I also want to emphasize the difference between domestic medicine and imported medicine. Many of the imported drugs we are talking about are produced by joint ventures of multinational pharmaceutical companies in China. Although strictly speaking, it should be considered domestic, these products are all produced according to foreign standards, under the brand name of foreign pharmaceutical companies, and enjoy the treatment of imported drugs in the eyes of ordinary people or in the pricing of hospitals, so I regard them as imported drugs. The domestically produced drugs I am talking about here only include drugs produced by state-owned enterprises.
I'd like to add that today we only discuss drugs from regular pharmaceutical factories, not counterfeit drugs produced by Sanwu Pharmaceutical Factory. Are there any fake medicines in China? I dare not say no, but at present, blatant counterfeit drugs should be very few. What you buy in a regular drugstore in a big city should be genuine medicine. If the store is found to be selling counterfeit drugs, the manager will be sentenced immediately. Counterfeit drugs belong to the event of "great public anger" and are usually dealt with severely and quickly. China's drug administration is still very strict in this respect.
So, how many kinds of domestic flat plates are there? According to the statistics provided by the US Food and Drug Administration, the total number of drug approval documents in China is as high as1890,000, of which chemical drugs1220,000, and more than 95% are generic drugs. In other words, at present, most of the domestic drugs in China's pharmaceutical market are generic drugs, so my question can be replaced by an almost equivalent proposition: where is the quality difference of domestic imitation tablets?
Is the quality of generic drugs poor? See what the government says. On 201February 13, the State Council issued the 12th Five-Year Plan for National Drug Safety, clearly stating that "the quality of some generic drugs is far from the international advanced level". This "Program" proposes to evaluate the quality consistency of generic drugs approved before the implementation of the revised Measures for the Administration of Drug Registration in 2007, and to evaluate the quality consistency of generic drugs and generic drugs in batches, of which 570 kinds were included in the national list of essential drugs and commonly used clinical chemicals before 20 15. These 570 kinds of commonly used drugs involve 2,400 enterprises, with an approval number of 33,000, more than 90% of which were in 2007.
The quality of generic drugs approved before 2007 cannot be guaranteed. There may be good or bad, and the government doesn't know. You are lucky to eat good food, but you are unlucky to eat bad food. Our government has realized this problem and decided to re-evaluate the generic drugs approved before 2007. But this work is very difficult, and it should be done in several steps. The first step is expected to be completed before 20 15, so the quality of the domestic drugs you are taking now, especially those approved before 2007, is not guaranteed.
If you don't trust the government, I'll give you another number. According to the WHO Statistical Yearbook published in 2009, the number of varieties entering the WHO procurement catalogue in China is 6, while that in India is 194, far exceeding that in China. The fundamental reason for this huge gap is that the quality of most generic drugs in China does not meet the requirements of WHO. You know, most drugs purchased by WHO are used in Africa, so there has always been a joke that China-made drugs don't even eat African refugees.
Although this joke sounds ridiculous, I can't help but say that it does make sense.
Many people will be surprised to hear this. China is a big manufacturing country, which is also dubbed as "a big cottage country". Although indecent, it is quite vivid, because China people's strong imitation ability is recognized all over the world, which is actually not a bad thing. Imitation is also an ability. In terms of medicine, China's pharmaceutical market is huge, with the scale of generic drugs approaching 500 billion RMB, which is also recognized as the largest market for generic drugs in the world. But why can't China's generic drugs even compare with India, which we have always looked down upon? To answer this question, we must start with the history of generic drugs.
Generic drugs are a very special commodity, because drugs have two unique properties. First, the quality of the same medicine from different sources should be the same, and it cannot be divided into different grades like gasoline. 92% and 95% correspond to different prices, which is ethically unreasonable. Second, the pharmaceutical industry is a highly regulated industry. Drugs can't be listed and sold casually, and they can't be priced freely after entering medical insurance. In the early years, people didn't understand these two unique attributes, and the generic drug industry didn't develop. It was not until the United States passed the Amendment to Drug Price Competition and Patent Period in 1984 that the problem was fundamentally solved. Therefore, the medical community believes that 1984 is the first year of global generic drugs.
Generally speaking, this amendment solves a unique contradiction in the pharmaceutical market, that is, the contradiction between encouraging innovation and safeguarding public interests. On the one hand, if we don't give innovators a certain market monopoly and high profit feedback, no one will innovate, and then we will have no new drugs to eat. This is easy to understand. On the other hand, if the protection is excessive, the price of drugs will remain high and the public interest will not be protected. A very special attribute of the latter medicine is that TV sets do not have this problem, so don't buy them if you can't afford them, which has little to do with public interests. Medicine is not good, because medicine is covered by medical insurance in many countries. The drug price is too high, not only the people will not agree, but also the government will not agree.
The details of this amendment are very complicated, so I won't say much, just give you a brief introduction from the perspective of generic drugs. The core of this revision is to answer the core question "How to measure the equivalence between generic drugs and patented drugs". As mentioned above, drugs cannot be graded, and generic drugs must be proved as safe and effective as patented drugs before they are allowed to go on the market. The patented drug has passed the strict phase I-III clinical trial, and there is no problem with its safety and effectiveness. But if generic drugs are retested in clinical trials, it will be too wasteful and unnecessary. Therefore, after consulting various experts, the FDA of the United States thinks that "bioequivalence test" can be used as a measurement index, which saves a lot of money for generic drug manufacturers.
What is "bioequivalence"? Actually, the explanation is very simple. What works in the patented medicine is a small molecule compound, so if the molecular formula and crystal structure of this small molecule compound of generic medicine and patented medicine are exactly the same, and their kinetic behavior in blood is also very similar, then they can be considered bioequivalent regardless of the curative effect. The amendment stipulates that generic drugs can only be allowed to be listed as substitutes for patented drugs if they pass bioequivalence tests. Conversely, once the generic drug has passed the bioequivalence test, we have reason to believe that it is completely equivalent to the patented drug in curative effect and can replace each other. However, a senior person interviewed by China Drug Evaluation Center told me that Chinese drug regulatory agencies and doctors don't understand the concept of generic drugs, and they don't understand the relationship between generic drugs and patented drugs. They thought that there was a difference in treatment standards between the two, and the result could be imagined.
On the other hand, overseas, the amendment gave birth to a phenomenon called "patent cliff". Take the United States as an example As soon as the patent for patented drugs expires, generic drugs will come out immediately. The price is much lower, but the curative effect is the same as that of patented drugs. The two can completely replace each other. Therefore, American pharmacists can safely prescribe generic drugs to patients. Except in very special circumstances, the payer of drugs, that is, medical insurance institutions, etc. Pharmacists are also encouraged to prescribe generic drugs to patients to save medicine costs. In this case, there is almost no way out for patented drugs, unless the price is also greatly reduced, which is similar to generic drugs, but this often means losing money, at least the profit is very low. Therefore, in many cases, as soon as the patent of the patented drug expires, the pharmaceutical factory will even stop production immediately, and sometimes the whole department will be revoked, and the relevant personnel will turn to research and develop new drugs. Therefore, this amendment will kill two birds with one stone. On the one hand, it encourages innovation, on the other hand, it reduces drug prices and protects public interests, and finds a good balance between the two.
However, this kind of patent cliff has never appeared in China, and imported new drugs can still be sold at the original price in the China market long after the patent expires. Not only that, imported drugs can also enjoy the so-called "super-national treatment" of separate pricing when bidding for drugs, resulting in the price of domestic imported drugs being several times that of domestic generic drugs. Please note that at this time, imported drugs can no longer be called patented drugs, so China's pharmaceutical industry has given those patented drugs that have passed the patent protection period a new name, called "original research drugs", to distinguish them from domestic generic drugs. This word is unique to China. There is no such thing abroad. They have only two terms: patented drugs and generic drugs. The difference between them is patent, but the quality is the same.
I have been talking about the theoretical problems of domestic generic drugs. Let me talk about generic drugs from a technical perspective first. As mentioned above, bioequivalence is the gold standard to judge the quality of generic drugs. Technically, this bioequivalence involves two parts. The first is that the small molecules that work must be the same, and the second is that the behavior of small molecules in the blood should be similar. Let's look at these two aspects respectively.
Small molecules, we refer to the patented chemical molecules, whose professional name is "pharmaceutical active ingredients", and the pharmaceutical industry prefers to call them "raw materials". In the eyes of ordinary people, this must be the most important step in the manufacturing process of generic drugs. In a way, this is of course right. This is the core of generic drugs. If you can't make small molecules, what else can you make generic drugs? Or if a small molecule is wrong, it becomes a fake medicine, so I won't discuss this. The early generic drugs in China really started from this small molecule, because it was difficult to buy imported drugs in China before the reform and opening up, but the literature could still be found, so the technicians of China Pharmaceutical Factory started with the chemical molecular formula printed on the literature and tried to synthesize it. This is how the era of generic drugs in China began. Of course, synthesizing raw materials is not an easy task, but there are many excellent chemists in China. Everyone solved the problem collectively and soon got the hang of it. Now it can be said that they have basically mastered this craft.
In addition, everyone who knows chemistry knows that the synthesis of this small chemical molecule from scratch definitely needs many steps. After each chemical reaction, the product should be extracted, and then the next chemical reaction should be carried out, and so on. If the purification step is not good enough, or the reaction is incomplete, some by-products will be left, which is the main source of impurities that most people say. Of course, this is a big problem, and the domestic imitation pharmaceutical factories are not good enough at this point, but because the relevant state departments attach great importance to this problem, the impurity problem has been basically solved in previous years.
In fact, the raw materials produced by enterprises in China have always been exported, but you must not think that this means that China generic drugs have gone abroad, which is almost two different things. Raw materials belong to chemical products, not pharmaceutical products, and their value accounts for a very low proportion in medicines. The raw materials produced in China are sold to imitation pharmaceutical factories in Europe, America, India and Israel at extremely low prices, while the drugs produced by others are sold to the whole world at extremely high prices. This is the current situation of the world generic drug market. China can only be regarded as a big producer of APIs, not generic drugs. India is much better than China in this respect. China has actually become a raw material supplier for Indian pharmaceutical companies, at the bottom of this generic drug ecosystem.
There is also a thorny problem, that is, the pollution problem in the production of APIs is difficult to solve, and the cost of eliminating pollution is high, so foreign pharmaceutical companies are unwilling to do it. Let us do it, which is equivalent to leaving environmental pollution at home and giving profits to foreign countries.
What I just said is the first step in the production process of generic drugs, that is, the production of APIs. The raw materials are only the active ingredients in tablets. They are not drugs, not commodities. Commercial drugs need to be packaged and transported, so they must be able to withstand certain environmental changes, pressure resistance, stability and so on. Therefore, raw materials must be combined with excipients to form solid preparations, that is, tablets, which we often say, before they can be listed.
On the other hand, we bought tablets from the pharmacy and swallowed them. First, they disintegrated in the digestive tract, then the active ingredients were dissolved out, and finally they were absorbed by the gastrointestinal tract and entered the blood. If this process is too slow, the tablets will be discharged before the active ingredients are completely dissolved, and the efficacy will not be exerted at all. However, if this process is too fast, for some drugs, it may also lead to the absorption of effective components too fast, which may bring some side effects on the one hand, and may not last long enough on the other hand.
This is the key to the bioequivalence test we mentioned earlier. Bioequivalence tests are usually carried out in healthy young and middle-aged men. Generally, about 20 such volunteers are found to take medicine according to the doctor's advice, and then blood is drawn regularly to measure the concentration of effective components in the blood, and a drug-time curve is drawn, with time on the horizontal axis and concentration on the vertical axis. The same volunteer took patented drugs and generic drugs successively, and drew drug-time curves respectively. If the difference between the two drugs is less than 20%, we think the two drugs are bioequivalent. Of course, this 20% is to tell you a concept, which contains many technical details, so I won't go into details.
Bioequivalence test needs real people, so it is very expensive. Another alternative method, called in vitro dissolution test, was proposed. To put it simply, this is to add a medium to a container at 37℃ to simulate the environment of human digestive tract, and then measure the dissolution curve of a tablet in the medium and compare it with the original medicine. Theoretically, this method can simulate the internal environment of patients with great differences in digestive ability, but bioequivalence test is still considered as the highest international standard. In vitro dissolution test has an advantage, which is very easy to do and low cost, and can be calibrated at any time when studying the manufacturing process.
Speaking of this, some people may ask, is there really such a big difference in the absorption rate of a tablet when it is eaten in the stomach? The answer is true, because there are many tricks in the production process. Patent drugs will definitely disclose the molecular formula of active ingredients when applying for patents, but the production process is confidential. What the imitation pharmaceutical factory should do is to reverse engineer the patented drugs, that is, to restore the production process of others step by step, and finally produce generic drugs that are bioequivalent to others. Of course, the process may not be exactly the same as others, but the final result must be excellent. This manufacturing process is the real difficulty in the pharmaceutical industry, and the technical content is also reflected here. Unlike synthetic raw materials, this project can only be completed by excellent chemists fiddling around in the laboratory, but it is a systematic project. To say a vulgar thing requires a deep industrial background, which cannot be improved at once. What China lacks is this background, which is the main reason why China can imitate other things, but not medicine.
This situation also exists in other industries, such as automobiles, but the domestic quality is just not good. The problem lies in the particularity of the medicine I mentioned earlier. Domestic cars can be sold at low prices. Is drugs okay? At least not in theory.
An engineer I interviewed used an image metaphor to explain this matter. He said that pharmacies are like steamed buns. You can use the same flour, the same yeast and the same stainless steel steamer as others, but because the technology is not in place, it is likely that a pot of dead pimples will be steamed in the end. In the past, the US Food and Drug Administration in China only looked at the final ingredients when evaluating the quality of generic drugs. It passed at the sight of flour, but it was far from it.
Looking back at history, we can know that the fault of China's imitation pharmaceutical industry lies in Zheng Xiaoyu. China entered the WTO on 200 1, so it can no longer steal other people's patented drugs, and can only make generic drugs. Under the auspices of Zheng Xiaoyu, the former US Food and Drug Administration promulgated China's first Measures for the Administration of Drug Registration in 2002. Since then, the generic drug industry in China has entered a crazy period. Everyone is desperately applying for projects and trying to get as many approvals as possible. This trend continued until mid-2006, when the former US Food and Drug Administration issued too many licenses in just four years, laying a hidden danger. Later, as we all know, Zheng Xiaoyu caught the news and was shot soon.
Now it seems that this "Measures for the Administration of Drug Registration" is full of loopholes. Although this method also requires oral solid preparation for bioequivalence test, the standard is very low and the comparison object is not fixed. One more thing about this: foreign countries require that generic drugs must be compared with patented drugs, but China can take approved generic drugs as reference preparations. As mentioned above, the drug-time curves of patented drugs and generic drugs can be considered bioequivalent as long as the difference is within 80%. But if the next generic drug is compared with the generic drug, and the two are multiplied by 80%, it may be much worse, so step by step, to the fifth 10.
More crucially, this "Measures for the Administration of Drug Registration" left too much room for manual operation in the process of application and approval of generic drugs, making counterfeiting extremely easy and convenient, making it easy for production enterprises to get away with it, resulting in a large number of enterprises that did not have the ability and qualification to produce generic drugs. According to statistics, 95% of the existing189,000 drug marketing licenses in China were issued before 2007 and distributed in the hands of nearly 5,000 pharmaceutical companies. At present, almost any pharmaceutical factory in China has dozens or even dozens of licenses, and there are dozens or even hundreds of enterprises producing the same drug. In order to survive, these enterprises engage in vicious competition in bidding. If they can't do it anymore, change their licenses.
This phenomenon is unique to China. No country has so many pharmaceutical factories as China, which is an order of magnitude worse. This is the fundamental reason for the poor quality of generic drugs in China. Some people may say that competition is not a good thing? With so many pharmaceutical companies competing with each other, consumers will certainly benefit. This view may be correct in other industries, but it is not effective in the pharmaceutical industry. The reason is that medicine is not a freely competitive industry. China adopts the policy of national bidding, and medical insurance pays the bill. The result of bidding is to drive down the drug price desperately. China's pharmaceutical companies can survive in this environment because of local protectionism in China, and all localities can have a certain proportion of flexibility in bidding, and this share is basically given to local pharmaceutical companies. In addition, the national standards are not strict, and the final result is that everyone sacrifices quality to fight for price. That's how poison capsules come from, because they can be cheaper by a few cents, which is probably the only profit point.
Many people are excited when they see the word poison capsule, which is considered to be the main reason for the poor quality of domestic drugs. In fact, this toxic effect is really small, and everyone ignores the more critical factor, that is, bioequivalence is far from imported patented drugs. In other words, the drug you are taking is probably insoluble at all or has a low solubility. All you have to do is go through the motions in the digestive tract and then pull it out directly. This is the main reason for the poor quality of domestic drugs. At this time, many consumers are still demanding lower drug prices. They didn't realize that it was at the expense of quality. In fact, the price of domestic drugs is not high. The reason why some people think it is high is because China's policy of "taking medicine to support doctors" is not to blame pharmaceutical companies.
Is the China government aware of this matter? Of course, the consistency evaluation of generic drugs I mentioned earlier is a correction of this matter by the government, and it can be said that it is a remedial lesson in history. However, I heard that the re-evaluation work is not going well, because everyone knows that if we want to be serious, we must cut off a number of unqualified pharmaceutical companies. But now pharmaceutical companies are big profits and taxes everywhere, belonging to state-owned enterprises and employing many workers. Dare you cut them? An insider told me a funny metaphor, saying that the current policy is that people would rather go online to scold their mothers after dinner than go out to scold their mothers after breakfast. If a large number of local pharmaceutical factories are cut down and workers are unemployed, who will be responsible for cursing women in the streets after breakfast?
After talking for a long time, I went back to the old problem, that is, the relationship among the government, enterprises and consumers in China has not been straightened out. Taiwan Province Province also encountered this problem in the early 1980s, but Huang, the leader of Taiwan Province Province at that time, resisted the great pressure of local forces and quickly reduced the number of pharmaceutical factories in Taiwan Province Province from 550 to 163 in just a few years, greatly improving the quality of generic drugs in Taiwan Province Province.
Of course, the situation in Chinese mainland is much more complicated than that in Taiwan Province Province, and the resistance to reform is much greater. However, medicine is a special commodity related to the health of the general public, which occupies a very high share in the national financial expenditure and has great market potential in the future. Can we start with this key industry and make bold reforms to set a benchmark for the reform of other industries? Let's wait and see.