In recent years, drug chaos has been frequently reported in newspapers: "India's first anti-cancer drug buyer" has been involved in the judicial whirlpool, foreign drugs have become "necessities" in the shopping list of Chinese people, and domestic generic drugs are "safe but ineffective" ... One of the important reasons is the stagnation and confusion of drug approval in the past decade.
Since 20 15, a flurry of reform has swept the entire pharmaceutical industry, from the second release of about 200 documents, to the broken wrist self-examination of clinical data, to the stimulation of new drug innovation ... Whether it is successful or not will directly affect the safety and quality of medication for everyone in China.
For more than a year, "No.44 Document" has become a hot word in the medical field.
On August 8, 20 15, 18, the opinions of the State Council on reforming the examination and approval system of drugs and medical devices (Guo Fa (2065438+05) No.44) was issued. This heavy document of about 4,000 words announced that the biggest drug approval reform in China in recent ten years surfaced.
March like a storm. By the end of 20 16, in just 16 months, China Food and Drug Administration (hereinafter referred to as the General Administration of Food and Drug Administration of the United States) issued about 200 policy documents, which made the industry dizzying.
"Feelings and joy are intertwined." After reading Circular No.44, Tang, president of Shanghai Food and Drug Safety Research Association and former deputy director of Shanghai, said that for many years, due to obstacles such as unsatisfactory system, insufficient mechanism innovation, and malpractice of administrative system, society and industry have many "criticisms" on the current drug supervision, and now it has finally broken the dullness and lag for many years.
Many bosses of pharmaceutical companies lamented to the Southern Weekend reporter that "spring is coming", and some people felt that this time "playing big". There is a message in the medical circle forum: "It is commendable that the General Administration dared to stir up a hornet's nest, but at the same time it stabbed several others, and I don't know how to end it."
This reform storm involving national drug safety and sweeping the whole industry is bound to bring pain and reshuffle.
The reform storm has achieved initial results. On June 2, 20 17, the General Administration of Food and Drug Administration of the United States announced that the backlog of drug registration applications in China had dropped from nearly 22,000 at the peak of 20 15 to 8,863 at the end of 20 16. Applications for clinical trials of chemical drugs and vaccines, as well as applications for registration of traditional Chinese medicines and ethnic medicines, were reviewed within a limited time. Give priority to 146 innovative drugs with obvious clinical value, drugs urgently needed in clinic, drugs with expired patents and the first generic drug in China.
"This is much faster than the reform in the United States." Dr. He Ruyi, chief scientist of the Drug Evaluation Center (CDE) of the US Food and Drug Administration, told Southern Weekend reporter. After leaving the US Food and Drug Administration (FDA) and returning to China for half a year, he deeply felt the fierceness of this storm.
"July 22 massacre"
This reform storm began with "tragedy".
The first incision was made in clinical trials. Modern medicine is the era of drugs to some extent, and clinical trials are the only way to verify safety and effectiveness.
One month before Document No.44, the General Administration of Food and Drug Administration of the United States issued the Announcement on Self-inspection and Verification of Drug Clinical Trial Data. The announcement requires 1622 clinical trial items to conduct self-examination, and voluntarily withdraw if there is any problem. If the report is not submitted or withdrawn within the specified time, the General Administration will conduct flight inspection. Once the problem is found, the application will not be accepted within 3 years, and the qualification of the drug clinical trial institution will be revoked and blacklisted.
This is called "the strictest data verification requirement in history". The industry calls it "July 22 tragedy".
Within the time limit of high-pressure self-inspection, executives of large and small enterprises are making choices, and some projects have been queued for a long time and are finally coming. "At first, I didn't know the scale of the government inspection. What worries me most is that I am afraid that I will not withdraw, and the consequences will be unimaginable. " A senior European pharmaceutical company told Southern Weekend reporter.
Soon, the "scale" saw the real seal. Only clinical trials have verified this item, and the US Food and Drug Administration has issued 26 announcements. Under high pressure, clinical trials are like falling dominoes. 1622 registered applications, about 80% people voluntarily withdrew, and 30 people were rejected. 1 1 institutions put on record for investigation, and those suspected of committing crimes are handed over to public security organs for handling.
The problems are listed one by one: the control drug is untrue, the experimental drug is untrue, and the bioequivalence test is fraudulent. In Phase II and III clinical trials, it was found that there were data modification, omission or failure to report to serious adverse events according to relevant procedures.
Public opinion is in uproar, but this is not surprising.
"In the past, the supervision of the clinical research process was very weak." Shao Rong, dean of the Graduate School of China Pharmaceutical University, who is deeply involved in drug audit reform, said that in the past, drug supervision has always been "re-licensing and light process". Some enterprises feel that listing profit is in sight when they get clinical approval, which leads to uneven quality of clinical trials.
The atmosphere is obviously tense. Some hospitals and clinical trial bases no longer accept new trials, while other clinical trial projects have increased costs due to lack of resources. According to the company, only the consistency evaluation test of generic drugs (the comparison between the efficacy of generic drugs and the original drug) soared from 300,000-500,000 yuan to 5,000-6,000,000 yuan.
After the "July 22 tragedy", a clinician said that clinical trials were largely standardized. The number of "irregular small enterprises" and "false data" has been greatly reduced, which has also laid the foundation for the subsequent reforms such as "conformity evaluation of generic drugs", "declaration of a batch of generic drugs" and "simplification of clinical declaration procedures for new drugs".
"This time I hit the snake seven inches," commented a department-level official of the medical system. Everyone knows what the problem is, but it is the first time to dare to do anything serious.
However, some doctors think that the reform can be more thorough. "Now it's just a corner of the curtain." Li Yong, director of the Department of Cardiology, Shanghai Huashan Hospital, suggested that more unannounced visits should be made and the problems should be investigated immediately after verification.
Ten-year "slow lane"
In the past 15 years, China's drug approval has experienced several roller coaster changes.
Since Zheng Xiaoyu, the first director of the US Food and Drug Administration, was sentenced to death for accepting bribes in 2006, drug approval has changed from "fast" to "big traffic jam". In the past ten years, public criticism of "lagging drug approval" has been endless.
According to industry statistics, 2007-2009 was a recovery period, and basically no new drugs were approved; From 2009 to 20 13, the approval number of chemical drugs (including new drugs and generic drugs) showed a linear downward trend. In five years, 2,663 domestic drugs were approved, accounting for less than 2% of the total market at that time.
"In those years, the government's orientation was to approve fewer drugs, be cautious and cautious, and enterprises were miserable." The owner of a pharmaceutical company in Beijing who asked not to be named said.
"The directors were all shot." An official of the US Food and Drug Administration admitted to the Southern Weekend reporter that the pressure was too great. Before this reform, some officials in the drug supervision system even refused to participate in academic exchanges. "People will say that so many medicines have not been approved yet, and there is still time to participate?"
The price of being too cautious should be borne by everyone. On the one hand, there are low-level domestic generic drugs in the market, and some people in the industry with a little medical background will choose not to use them because they may be "safe but ineffective"; On the other hand, a large number of foreign new drugs can't enter, and illegal purchasing is rampant. Lu Yong, the first person to purchase anticancer drugs in India, was involved in the judicial whirlpool because he helped patients buy Indian generic drugs for leukemia. The question "Why China people can't get new drugs" has been repeatedly raised by the media.
Almost every year at the National People's Congress, there are a large number of proposals aimed at the difficulty of drug approval. At the symposium of medical representatives on 20 15, five NPC deputies highlighted this dilemma and thought that "China people take new drugs 8- 10 years later than foreign countries on average". At that time, the US Food and Drug Administration explained the difficulties, but everyone did not buy it. In the eyes of enterprises and the public, it is the real demand to approve and use drugs well.
Subsequently, Wu Xun, deputy director of the General Administration of Food and Drug Administration of the United States, promised that the General Administration planned to digest the drug approval stock in three years and balance the increment. Half a year later, this reform storm quietly kicked off. This is also the proposition of Bi Jingquan 20 15, Director General of the US Food and Drug Administration, after taking office in June.
According to his resume, Bi Jingquan joined the State Planning Commission (the predecessor of the National Development and Reform Commission) from 65438 to 0984. During his tenure, he repeatedly expressed his views on drug prices and said that "the reform of drug prices must be promoted". His transfer is also considered to be related to the reform of the drug price management system.
"I am very courageous and dare to take responsibility." This is the unanimous evaluation of Bi Jingquan by people inside and outside the industry.
The most critical reform link
It is too difficult for pharmaceutical companies to develop new drugs. Domestic pharmaceutical companies often adopt a more prudent strategy-copying foreign drugs. As the second largest drug consumption market in the world, China currently has about 6,543.8+0.8 million drug approval numbers, of which 6,543.8+0.2 million are chemical drugs, of which more than 95% are generic drugs, such as aspirin, and the approval number is 688.
"A considerable number of these drugs were declared by Zheng Xiaoyu (former director of the State Pharmaceutical Products Supervision and Administration) during 2006-2007, and some generic drugs have quality problems in all aspects." An industry insider who asked for anonymity said.
Generic drugs are not equal to inferior drugs. The problem is that in the United States, generic drugs should be "identical to the original drug in terms of active ingredients, dosage, safety, curative effect, action (including side effects) and diseases targeted", and the reference drug for comparison must be the original drug. But in China, the definition has changed. Before 20 15, drugs that were not produced and marketed in China were new drugs; Drugs that have been included in the pharmacopoeia standards are generic drugs. Therefore, the reference drugs of many generic drugs in China are relatively early generic drugs made by other domestic manufacturers, which is "out of shape".
A reviewer of a drug testing center remembers that it was once the "hidden rule" of the whole industry not to pursue curative effect but only to care about safety. At an expert meeting to review a child's drug, a big-name expert urged: "What can't be approved? I have used so much and never had an accident. "
The consistency evaluation of generic drugs "everything starts with the original preparation" is precisely to change this situation. From 2065438 to March 2006, the General Office of the State Council issued the Opinions on the Consistency Evaluation of the Quality and Efficacy of Generic Drugs, requiring pharmaceutical companies to evaluate the consistency of quality and efficacy between generic drugs and original drugs.
"The era of only paying attention to safety and ignoring benefits will eventually pass." Some pharmaceutical researchers lamented that this was the most difficult and crucial step in a series of reforms.
According to the regulations, the consistency evaluation should be completed before the end of 20 18 for the oral solid preparations of chemical generic drugs approved for marketing before June 10, 2007 in the National Essential Drugs Catalogue (version 20 12), and for the varieties that need to carry out clinical efficacy tests and have special circumstances, it should be completed on 20 18. If it is not completed within the time limit, it will not be registered again.
The drug testing center made its first active appearance.
If the purpose of self-examination and verification of clinical trials and conformity evaluation of generic drugs is to avoid the easy listing of harmful or ineffective drugs, then changing the definition of new drugs, opening up the marketing license system (see the first case of drug marketing license system approved in Southern Weekend 2065438+20071October 6) and giving priority to review will open the door for new drugs to enter the market.
In recent years, it is not uncommon for Chinese people to travel abroad and buy medicines. Everything from cancer drugs to small drugs for colds, coughs, headaches and brain fever has become a "necessity" on the shopping list.
According to the data of Drug Testing Center, only a few dozen innovative drugs (referring to the most primitive new drugs) have been approved for listing in China in the past decade. Among the new drugs that have been listed in China, only three have entered the clinical trial stage in the international market at this stage, and there are no listed drugs.
In the past six months, the thinking of the General Administration of Food and Drug Administration of the United States has also been changing from a system based on generic drug evaluation to paying equal attention to generic drugs and new drugs.
Document No.44 changed the standard of new drugs from "drugs not listed and sold in China" to "drugs not listed and sold inside and outside China". Changing the word is to raise the threshold of new drugs and change the dilemma of "new drugs are not new" Moreover, pay more attention to the evaluation of clinical value.
In the past, imported drugs had to be re-tested in China, but few people could participate. He Ruyi said that in the future, enterprises will be encouraged to expand clinical trials and include some critically ill patients who do not fully meet the test standards, so as to maximize the benefits for patients.
The phenomenon that clinical trial institutions can't find anywhere will be gradually solved with the relaxation of institutional accreditation. 20 17 10 12, the State Council issued a document to cancel the provincial preliminary examination policy of clinical trial institutions. Consistent with the thinking of the industry, He Ruyi hopes that the future clinical trial bases can learn from the full liberalization of the United States and let the market adjust the relationship between supply and demand, rather than just being placed in top three hospitals.
As the core technical department of this reform, the drug testing center is also changing.
The number of personnel in the drug testing center has increased from more than 100 at the beginning of 20 15 to about 600 at present (including temporary staff of the provincial bureau), and it is planned to increase to 1500 in 2020. "That will be enough." He Ruyi said. His position as chief scientist is also the first time in history.
He Ruyi said that policies are being formulated, hoping to provide one-on-one supervision services for some drugs with significant potential, breakthroughs in major diseases and obvious improvements in existing treatment schemes, so as to help enterprises jointly design and formulate better processes in clinical trials.
It is understood that the drug trial center has held more than 60 communication and exchange meetings on innovative drug research and development.
20 17 65438+ 10/0/8, Southern Weekend reporter went to the drug testing center for an interview. On the same day, they held the first symposium to which people from all walks of life were invited. Although only ten units have been opened, a clear signal of "openness, transparency and cohesion" has been released.
Too hard?
In the field of medical care and medicine, many famous reforms that are not uncommon have been stranded because of "changing the top without changing the bottom". Some of them have stagnated because of the resistance of reform, and more will be shelved because people are already in politics.
"This time it is a very solid reform, not a movement, but a systematic and step-by-step reform." YueYang, a professor at the School of Business Administration of Shenyang Pharmaceutical University, commented that she participated in the revision of the Drug Administration Law.
Drug Administration Law 200 1 has been revised for 16 years. Some people therefore question that the Drug Administration Law has not been reformed as a superior law, and there may be implementation problems in this drug approval reform.
However, scholars believe that it takes too long to amend the law, and the reform may be delayed indefinitely when the law is finalized. "This is a process of dynamic balance. Many problems encountered in the reform will be discussed in time, and finally whether it will rise to law will be considered. " Shao Rong said that the newly revised Drug Administration Law began at the end of 20 13 and is still continuing. ...
Other issues may be more realistic. In the interview, Southern Weekend reporter found that some people in the industry felt that the reform came too fast, and some "pushed too hard", and different understandings of the reform also made all parties at a loss. In Taizhou Medical City, Jiangsu Province, at a recent media meeting, local enterprises complained about many difficulties.
"I feel fine, don't worry? We will adopt the reasonable opinions of enterprises soon. Otherwise, if we wait, we will not be able to discuss it over and over again. " He Ruyi said.
"Many reforms have no cost." YueYang explained that the government does not have a system to measure how much social cost will be consumed when the reform is implemented. This leads to "the policy is good, but the implementation path is wrong". For example, you wouldn't expect that the self-examination of clinical trials would lead to a tenfold increase in trial costs. She suggested that a third-party organization should carry out policy measurement and effect evaluation to ensure the best effect of implementation.
To some extent, this reform is a road to return.
First, the return system itself. According to Tang, the above-mentioned president of Shanghai Food and Drug Safety Research Association, in recent years, the regulatory authorities and many enterprises have been "slack", and now all parties should return to the "due state" that originally required the implementation of the system and ensured the quality and safety of drugs.
The second is to return to scientific supervision. Shao Rong feels that the legal awareness of the regulatory authorities has been significantly enhanced. Among the various laws and regulations introduced, they will first check whether they will conflict with existing laws and regulations. If there is a conflict, ask NPC for authorization to solve it.
Reform will continue. When asked when it would be completed, Shao Rong thought for a moment: "This is a reform without time coordinates. Encourage innovation, improve quality, and always be on the road. " However, she hopes that society must give regulators enough space. If the risk of doing is higher than inaction, then no one will be willing to reform for the benefit of more people.