Drug review reform will trigger a major reshuffle of drug companies, most generic drugs or out of the game.
China's pharmaceutical manufacturing industry is experiencing a storm.
The eye of the storm is the "Opinions on Reforming the Review and Approval System for Drugs and Medical Devices" (hereinafter referred to as the "Opinions") promulgated by the State Council on August 18. The Opinions aim to improve the quality of generic drugs and encourage the development of innovative drugs. The opinion is a programmatic document, which has guiding significance for the upcoming "Regulations on the Implementation of New Drug Management Measures" and the new version of "Drug Registration Management Measures.
The more consistent view in the industry is that the State Council approved the reform of the review and approval system for drugs and medical devices in order to carry out a bone-breaking reform in the system. For innovative and generic drug companies, the former will enjoy multiple conveniences, while most of the latter may be eliminated.
Most generic drugs will be out
The introduction of the "Opinions" is no less than an earthquake for generic drug companies, and most of them may be devastated. Wu Zhen, deputy director of the State Administration of Food and Drug Administration, said at a news conference of the State Council that he would strive to complete the quality consistency evaluation of national essential drug oral preparations and reference preparations by the end of 2018. The consistency evaluation of other generic drugs will be gradually solved within ten years. Generic drugs that fail to pass the quality consistency evaluation within the prescribed time limit shall be withdrawn from the market. The quality consistency evaluation was first carried out in generic drugs approved for marketing before the implementation of the Measures for the Administration of Drug Registration revised in 2007.
The quality consistency evaluation of generic drugs is a commonplace topic, why does the Food and Drug Administration repeatedly mention it? It is necessary to understand three questions: what is generic drugs, why 2007 is the node, and what impact will the quality consistency evaluation have on the industry?
To answer the above questions, we must first start with the current situation of China's generic drug industry. Data from the Food and Drug Administration show that there are nearly 190000 drug approval numbers in China, of which 122000 are chemical drugs, accounting for about 2/3, and the rest are traditional Chinese medicine and biological agents. Due to China's long-term backwardness in the development of chemical drugs and a serious lack of independent innovation, more than 95% of the 122000 chemicals are generic drugs. "According to the strict international definition of innovative drugs, I'm afraid 99% are generic drugs." Wei Guoping, chairman of Ogina Pharmaceuticals, said that in terms of quantity, China is definitely the largest country in generic drugs; in terms of quality, China is basically a country of copycats of generic drugs.
This is evident from the WHO's attitude towards generic drugs in China. According to the WHO statistical yearbook, only 6 drugs have entered the WHO procurement catalogue in China and 194 in India. What is more embarrassing to Chinese medicine (15.71, -1.75, -10.02 per cent) is that most of the drugs WHO purchases from China are used in Africa. In Wei Guoping's view, the lack of quality consistency evaluation is the main reason. In other words, WHO does not recognize the efficacy and safety of Chinese chemical (6.69, -0.74, -9.96%) generic drugs.
Why is it so important to evaluate the quality consistency of generic and original drugs? First, let's talk about what an original drug is, the international popular name for an original drug is a brand drug, which refers to the first company brand in the world to develop a drug. Before the original research drug is put on the market, it generally needs to go through strict animal experiments, human clinical 1. 2. three-phase experiments, and then the four-phase clinical amplification experiment proves that the curative effect is accurate, safe and reliable before it can be promoted to the market.
Generic drugs are a unique drug R & D and production system in the world pharmaceutical industry. It originated from the US Food and Drug Administration in 1984 and was later adopted by developed countries such as Europe and Japan. Wei Guoping explained that although my country has been producing generic drugs, in a strict sense, it was not until July 10, 2007, when the State Food and Drug Administration promulgated the Measures for the Administration of Drug Registration (Bureau Order No. 28), the quality of generic drugs in my country It began to be in line with international standards. At that time, 122000 chemical generic drugs had been registered and approved in accordance with the measures for the Administration of Drug Registration (Bureau decree No. 17) implemented on May 1, 2005, thus laying the root of the problem of the efficacy of generic drugs in China.
Therefore, 2007 is a watershed, and the attitude of the Food and Drug Administration is also very clear. The quality consistency evaluation work was first carried out in generic drugs approved for listing before the implementation of the revised "Drug Registration Management Measures" in 2007. Prior to this, generic drugs were compared in accordance with the "national standard for similar generic drugs", which means "mixed with water and then mixed with water. At the same time, before 2000, drugs were approved by all provinces, and the standards were inconsistent.
Wei Guoping said that the U.S. Food and Drug Administration stipulates that the dosage forms of generic drugs (such as tablets, capsules, oral liquids), the content of drugs (active ingredients, such as aspirin, acetaminophen, and ibuprofen), and the usage and dosage must not only be the same as the original The research drug is exactly the same, and the most important thing is that the efficacy must be consistent. If only the dosage form and drug content are the same but the efficacy is inconsistent, it cannot be called a generic drug, but a counterfeit drug or a counterfeit product.
Then, how to evaluate the consistency of the efficacy of generic drugs and original drugs? The practice is the internationally accepted human bioequivalence test. Select 18-24 healthy volunteers, double-blind test of the original research drug and generic drugs, through the statistical analysis of the drug content in the blood of the subjects, to determine whether the efficacy of generic drugs and the original research drug is consistent, requiring the similarity of the two to reach 80%-130. Figuratively speaking, generic drugs and the original research drugs have a mother-child "blood relationship", not only similar in appearance, but also similar in "DNA", otherwise it is "civet cat for prince".
But the objective situation is that the relationship between generic drugs and original research drugs in China has gone far beyond the "mother-child relationship". On May 1, 2005, Article 25 of the first national "Measures for the Administration of Drug Registration" (Bureau Order No. 17) stipulates that "to apply for the registration of chemical drugs with national standards, bioequivalence tests are generally conducted". The document emphasizes the principle of "general" rather than "must".
On July 10, 2007, the State Food and Drug Administration revised the measures for the Administration of Drug Registration, in which Article 74 stipulates that "generic drugs shall have the same active ingredients, routes of administration, dosage forms, specifications and therapeutic effects as the generic drugs". It is important to note that Chinese generic drugs refer to "generic drugs" rather than "original drugs". This is also the essential difference between generic drugs in China and internationally accepted generic drugs.
Generally speaking, international standard generic drugs can only be the relationship between "mother and daughter generation", while Chinese generic drugs can be the relationship between "grandmother and granddaughter two generations" and "grandmother and granddaughter three generations. Figuratively speaking, both generic drugs and original research drugs in China have the blood relationship of "five suits.
At this point, it is not difficult to understand why generic drugs listed before 2007 must complete the consistency evaluation with the original drug. Wei Guoping believes that very few of the 122000 generic drugs on the market can eventually pass the bioequivalence test with the original drug. In the process of development, the vast majority of generic drugs have not done systematic research on the prescription and process comparison with the original drug, and some have done it nominally, but there is an unspeakable concealment of fraud.
From this point of view, except for those pharmaceutical companies that have established a strong R & D team and can solve the technical problems in consistency evaluation by themselves, other pharmaceutical companies can only be eliminated. "Among the 4700 pharmaceutical companies in the country, 90% of small and medium-sized pharmaceutical companies do not have R & D centers, and the remaining 10% of large and medium-sized pharmaceutical companies have strong R & D capabilities." Wei Guoping said that quality consistency evaluation is a hurdle for all generic drug companies.
Innovative drugs enjoy many conveniences
At a time when generics are being hit, the innovative drug industry is starting to steal. The Opinions provide a lot of convenience for the review and approval of innovative drugs, aiming to speed up the pace of listing innovative drugs. The Opinions proposes to implement a special review and approval system for innovative drugs; accelerate the review and approval of innovative drugs for the prevention and treatment of AIDS, malignant tumors, major infectious diseases, rare diseases and other diseases, and drugs included in major national science and technology projects and national key research and development plans, Innovative drugs and children's drugs transferred to domestic production, as well as innovative drugs that use advanced preparation technology, innovative treatment methods, and have obvious therapeutic advantages.
At the same time, to carry out the drug marketing license holder system pilot. Drug research and development institutions and scientific research personnel are allowed to apply for registration of new drugs. When they are transferred to enterprises for production, they will only conduct on-site process verification and product inspection of the production enterprises, and will not repeat the drug technical review.
"From the drug review reform document issued by the State Council, it can be seen that the state's emphasis on my country's new drug research and development has risen to the strategic level. This means that China's pharmaceutical innovation will usher in a new stage of development. "Zhang Hua, head of research and development of a pharmaceutical company in Shanghai, commented on the landing of the above policy.
Zhang Lianshan, deputy general manager in charge of R & D of Hengrui Pharmaceuticals, said: "We appreciate the major reforms made at the national level in drug review and approval. This will greatly improve my country's pharmaceutical innovation environment and support innovation. Promoting the enthusiasm of domestic pharmaceutical companies for R & D and innovation is expected to have greater significance for the improvement of the quality level and the speed of listing of domestic new drugs."
In recent years, the country has been promoting the development of drug innovation in China at all levels, especially the innovative research and development of major diseases and clinically urgently needed drugs. Various policies have been introduced one after another, such as the promulgation and implementation of the "Regulations on the Administration of Special Approval for New Drug Registration" in 2009, the issuance of the "Instructions for the Definition of Special Approval Procedures for Biological Products" in 2013, and the "Working Procedures for Priority Review of Generic Drugs in Urgent Clinical Urgent Need" are also being formulated.
The successive introduction of this series of policies has brought effective promotion to the application and listing of products in China's heavyweight fields. As of March 11, 2015, CDE has 205 major special registered product acceptance numbers and 942 registered product acceptance numbers for special channels, including 391 import acceptance numbers and 551 domestic product acceptance numbers. Anti-tumor drugs are the most declared areas for special channels.
Among them, Hengrui Pharmaceuticals is the enterprise with the largest number of special approved varieties, clinical declarations and production declarations, and Hengrui has listed a class of new drugs, such as Irecoxib and Apatinib mesylate, which have been listed in China in recent years. In addition, Jiangsu Haosen, Zhejiang Haizheng and other special review and approval of products more enterprises.
"At present, the documents at the State Council level are mainly framework contents. It is believed that CDE will give more operational detailed documents, such as whether oncology drugs will adopt a filing system. Can the review and approval time be shortened to 2-3 months? How to define rare diseases and whether the state will support them in terms of price and tax. This kind of problem is our concern and expectation. "Zhang Lianshan told the China Securities Journal.
The specific details mentioned by Zhang Lianshan are also the core of Zhang Hua's attention as the head of research and development. Zhang Hua said that from the perspective of the development of rare disease drugs in the United States, follow-up support policies play a vital role in the speed of drug launch. In particular, the formal implementation of the FDA Safety and Innovation Act in 2012 has greatly accelerated the development and marketing of cancer drugs, orphan drugs and anti-infective drugs. Hongyuan Securities research report pointed out that in recent years, FDA approved drugs through special channels increased significantly. Of the 39 new drugs approved by FDA in 2012, 22 (56%) were approved through one of the special review items, and 9 (23%) were approved through more than two.
This means that the formulation of specific implementation rules may become a key factor in the speed of development in a certain field, and it will be more operational to give different plans for different situations. Zhang Hua pointed out that the current problems in the research and development of many disease drug use fields in China are different. For example, the obstacles to the research and development of children's drugs do not lie in the speed of review and approval, but in the difficulties of research and development, including clinical trials and drug pricing.
"At present, China's local R & D and innovation capabilities have made great breakthroughs in many fields. In the future, the state's encouragement and support for drug innovation can not only stay at the superficial level of direct project financial support. Formulating relevant policies to enable enterprises to see a more long-term development path and prospects, to make the environment more transparent, and to make policy planning clearer is what real R & D enterprises need most. "zhang hua said.
The Opinions have another bright spot in encouraging innovation: a pilot listing permit holder system. In the past, China's drug approval documents were bound to the qualification of pharmaceutical industry enterprises. If you are a scientific research organization and have developed a new drug, you can either sell it to the enterprise or invest in building a factory. There is no third way. Selling to an enterprise is a one-shot deal, and many researchers are not reconciled to it, and it is not conducive to continuous innovation; and investing in building a factory is actually a bit of a waste of resources, because the Chinese pharmaceutical industry currently seems to have excess hardware resources.
Wu Zhen explained, "the implementation of the listing license holder system enables our researchers and scientific research institutions to own the ownership of the product in the process of innovation activities. As long as they have the ownership, they can turn the product into capital, not simply a commodity, but capital, which can be invested, invested or commissioned. In this way, the vitality of innovation is greatly enhanced."
Clearing the review backlog
In recent years, the drug review cycle is too long, has been a chronic disease of the Food and Drug Administration.
Wu Zhen, deputy director of the State Food and Drug Administration, listed a set of figures: there are 21000 varieties of drugs under review, 90% of which are generic drugs. Further refinement, of which 8 varieties have more than 100 enterprises in the declaration; 23 varieties have 50-99 in the declaration; 89 varieties have 20-49 enterprises to declare. Wu Zhen said that the backlog will be initially eliminated in 2016. Achieve annual import and export balance in 2017; The review will be completed within the time limit in 2018.
The small number of reviewers is an objective reason for the long drug review cycle. Wu Zhen said that at present, the General Administration has received 8,000-10,000 approvals a year, but there are only 120 reviewers. The U.S. Food and Drug Administration has 5000 chemical drug reviewers alone, and only 3000 varieties are approved each year. In the future, "the evaluation center will mobilize resources with the help of social resources, including some scientific research institutions, colleges and universities, and the existing reviewers of the drug administration system. We can completely concentrate some technical forces here by purchasing services. "Wu Zhen said.
Prior to the issuance of the Opinions, the State Food and Drug Administration issued the Announcement of the State Food and Drug Administration on Soliciting Several Policy Opinions on Accelerating the Resolution of the Backlog of Drug Registration Applications (No. 140 of 2015) on July 31 (hereinafter referred to as "No. 140"). In view of the falsification of clinical data, document 140 gives severe penalties: inspectors in the process of drug review, found that the drug development data are incomplete and untrue, will not be approved; If it is found that clinical data is falsified, the person directly responsible in the applicant, clinical trial institution or contract research organization involved in the falsification shall be investigated and included in the "blacklist" to disclose relevant information to the public; the new drug registration application submitted by the applicant for falsification of clinical research data will not be accepted within 3 years; Clinical trial institutions and contract research organizations that participate in the falsification of clinical trial data will not accept the application materials of their participation in the research before the rectification and acceptance is completed; The clinical trial data of the person directly responsible for the falsification to participate in the research or organize the research will not be accepted within ten years.
The more unanimous opinion in the medical community is that these penalties are unprecedented in severity, and the determination at the highest level is evident.
Wei Guoping introduced that the falsification of drug registration application data is an open secret in the industry. From initial research data, production process data to clinical trial (including bioequivalence test) reports, a gray falsification industry chain has been formed, which has become an obstacle to my country. A cancer for the healthy development of the pharmaceutical industry. There are many reasons for the rampant fraud, including historical reasons, examination and approval management departments, and applicants, but the fundamental reason is the low overall technical ability of China's drug research and development team.
Liu Chunguang, assistant to the general manager of clinical research company Tiger Pharmaceuticals (30.740, -3.41, -9.99), said that the cleaning up of drug registration problems in document 140 is obviously good for mainstream pharmaceutical enterprises in the industry. Tiger has regarded this market rectification as a historic opportunity to further expand its business in the whole country.
At the same time, Liu Chunguang pointed out that in the past, large pharmaceutical companies organized large teams to make drug registration declarations and even implement clinical projects. From the principle of interest avoidance, outsourcing to third-party clinical research contract institutions is a better choice. And those small R & D enterprises, such as those who rely on helping enterprises to make declaration materials, may all be eliminated this time. In the process of industrial upgrading, the reshuffle of the industry is inevitable.
Liu Chunguang judged that after this round of clean-up and rectification, the market share of innovative drug R & D companies supported by capital will increase significantly. In the face of opportunities, clinical research companies like Tiger Pharmaceuticals, which are born in the domestic market, have a richer industrial chain than multinational enterprises, have a more agile response to the market, and have a stronger ability to adapt to the domestic environment to seize opportunities. The development prospects will continue to be promising.
Tan Bo, deputy general manager of Guangzhou Boji Pharmaceutical Biotechnology Co., Ltd., also believes that from the No. 140 document, we can see the determination and attitude of the regulatory authorities to solve the backlog of drug registration applications, and it also reflects the change from "blocking" to "sparse". The strategy of guiding and encouraging enterprise innovation to solve clinical urgent needs.