The "beautiful philosophy" of Chinese innovation

"No one can affirm where the pharmaceutical innovation in the midst of opportunities, cooperation, transformation and complex global competition will eventually go. But we know that history will not turn back; and no one can predict that in terms of wealth, policy, and technology Under the combined force of culture and culture, how much potential the pharmaceutical company has that can be stimulated. We only know that the future is always beyond imagination!" Tao Jianhong, deputy director of the Southern Institute of Pharmaceutical Economics and editor-in-chief of the "Pharmaceutical Economic News", is in an exclusive interview He said: "The premise of innovative thinking in the research and development of new drugs is a conjecture about market demand, and the market will refute this conjecture one after another. Those who have gone through rounds of market replies and constantly amended, Only those innovations that survive the adjustment are truly productive innovations." Then, how can the test tube and the counter be connected in the shortest time and at the lowest cost? Let us share Tao Jianhong's "beautiful philosophy" on the development of new drugs.

　　 The ability to keep the mind happy

　　Reporter: How is the current environment for new drug research and development at home and abroad changing?

　　Tao Jianhong: At present, countries all over the world are looking for ways to restructure their industries out of economic dilemmas. Innovation is known as the dynamic engine driving sustainable development. How to keep innovative ideas and R&D practices alive is a difficult problem. We are all familiar with the story of "Don Quixote". The personality of being paranoid about ideals and not afraid of sacrifice is somewhat similar to those who are lonely and persistent in innovative adventures. However, innovation does not welcome tragic heroes. The most important qualities of a scientist are optimism and tenacity. We must know how to enjoy the pleasure of pharmaceutical research. The first decade of this century was the “lost decade” of global new drug research and development-the pharmaceutical industry once entered a dormant period of high input and low output, and the value of every dollar invested in industry research and development has shrunk by 70%. 2005～ In 2010, the number of approved NMEs dropped by 40%. The number of NMEs approved by the FDA each year was only 22. The value of new drugs on the market was only 430 million U.S. dollars, a 15% drop from the last decade of the 20th century. With the expiration of "blockbuster" patents such as Lipitor, the total value of pharmaceutical companies has shrunk to more than US$50 billion. In addition, the global pharmaceutical industry is still relatively monopolized by leading companies in a few developed countries. The weak innovation of large companies has slowed down the overall growth rate of the pharmaceutical economy. In the next three years, the growth rate of the world pharmaceutical market will still hover at 5%. about.

Fortunately, we have begun to regain the "lost decade", and the global pharmaceutical innovation climate has picked up. In 2012, the R&D intensity of the top ten global pharmaceutical R&D companies averaged 15.5%, maintaining the usual level, especially It is China and other emerging market countries that have increased their R&D investment. According to our Southern Research Institute, during the "Twelfth Five-Year Plan" period, my country's drug R&D investment has increased by nearly 20.8 billion yuan annually, and the R&D intensity reached 3% in 2015.

　　 In 2013, there were two major policies that will bring positive energy to the research and development of new drugs. The more direct is the reform of the drug review system. We noticed that the 2012 drug review report that was disclosed a few days ago changed the rigid writing style of official documents and started with a humanistic voice, telling about the "thalidomide" incident. Revealing the powerful mission of new drug approval for safeguarding health, let the seemingly mysterious drug review close the distance with the public. At the end of 2012, Guangdong Province took the lead. The transfer of new drug technology, drug production technology transfer and part of the inter-provincial drug production business has undergone technical review and administrative approval at the provincial bureau. The National Center for Drug Evaluation has established a pre-clinical pharmacy evaluation template for innovative drugs and an annual report system during research and development, and the technical requirements for pharmacy are basically in line with international standards. The interpretation of related reforms will be presented by our "Pharmaceutical Economic News" with special planning.

　　 Another far-reaching influence is the national "Twelfth Five-Year" biological industry development plan. The 21st century is an era dominated by life sciences. China's life science industry has a large number of experienced technical talents and attracts the attention of venture investors. The Chinese government's support for the industry is also increasing year by year, and it is very likely that one day a unique drug development path will be formed to compete with the Western model. The Chinese government has allocated 160 billion U.S. dollars for new hospitals and clinics in the past three years, and has also made substantial investments in the construction of life science laboratories, biotechnology parks, and incubation centers. Various localities are also actively introducing incentive measures to increase the development of more than a dozen life industry parks across the country. At the same time, the electronic medical record management system for clinical research is also increasing investment in research and development, and a clinical database with a wide range of sources will be created.

　　The new Chinese government regards the dividends of reform, the vitality of innovation and the potential of domestic demand as the three major supports for building an upgraded version of the Chinese economy. Innovation itself needs to be activated. The classic work of American national science and technology policy, "Science: Endless Frontiers", requires the country to formulate policies to support scientific undertakings, and emphasizes the need to protect the spirit of free exploration in scientific research, and maintain the necessary tension between the government’s will and scientific freedom. . This concept seems to be imperceptible in China's pharmaceutical industry. Although the advancement is still very slow, new drug research and development in China requires a kind of optimism of "walking with the snail". The change begins with the adjustment of the developer's mentality.

　　 Let R&D bid farewell to the regretful experience

　　Reporter: You just mentioned the recovery of the innovation environment and the adjustment of innovators' mentality. Then, at the practical level, how to choose the right position in the new drug research and development project? Tao Jianhong: Literature is a regretful art, and its price is a sense of hunger for reading experience; but the regret of new drug research and development is often the time cost of more than 5 years and the loss of hundreds of millions of yuan in funds, even if the new drug successfully passes the approval threshold and goes on the market The security risks of subsequent mass use are still being tested, and a little regret in the early design will cost lives. Therefore, new drug development must be perfect, which requires that every step must be beautiful.

So, how to do a good job in the market analysis of new drug research and development projects, we might as well use the meaning of the word NICE in English to interpret. Specifically, N stands for novelty—innovation, I comes from lock-in—lock, and C is complementarity— Complementary, and E refers to efficiency-efficiency. These keywords generally cover the key points of market analysis in new drug research and development projects.

　　 We are accustomed to understanding innovation as innovation, which is a relatively macroscopic meaning, including new ideas, new inventions and new facilities. Innovation in a broad sense includes discovery, invention, and creation. Mankind recognizes objects or laws that exist objectively in nature. This is a discovery; using the discovered natural laws or scientific principles to propose a creative technical plan is an invention. And what is creation? Creation refers to the activity of humans using their brain and physical strength to produce unprecedented material and spiritual products that people need. In contrast, Novelty is more specific and microscopic. On the one hand, it emphasizes the novelty of things. In the pharmaceutical industry, it specifically refers to drugs with high technological innovation content, such as a class of new drugs in China; on the other hand, it emphasizes the compactness and economy of things. , This meaning fits with the positioning of our niche market (NicheMarket) in the development of new drugs.

　　Data shows that in recent years, the number of new chemical drugs for category 1.1 in China has basically remained at around 70, and the number of new drugs for category 3 has increased by nearly 100 each year. The state's policy of encouraging innovation has begun to appear in the structure of drug application. Since 1986, my country has approved nearly 40 self-developed Class 1 chemical drugs, an average of 1 to 2 per year. Excluding the special circumstances of the sharp increase in the number due to centralized review in 2008 and 2009, a breakthrough in the number of new Class 1 drugs in 2011 However, the number of modified dosage forms has shown a declining trend, and the number of generic drugs has also greatly decreased. This shows that companies are paying more attention to the development of new drugs. In the past, the low-level duplication of simply changing dosage forms in exchange for new approvals has been reversed.

　　 Nowadays, some of the fastest-growing pharmaceutical companies extensively utilize existing assets, skills and core competitiveness, concentrate on developing products or technologies, and work hard in a certain segment of the market to become "hidden champions." For example, more and more large pharmaceutical companies are involved in the rare disease drug market with small market scale but higher pricing. In China, one of the most promising niche markets is the development of pediatric dosage forms. Regardless of the age level, the demand for medicines is a rigid demand. Children are the future of the country and the center of Chinese-style families. Their drug needs have attracted more attention from the society.

　　 The prevalence of children is a basic indicator to measure the size of the "buyer" market in the children's drug market. Based on the total population of our country, it is estimated that the number of sick children in our country will reach more than 30 million every year. Among the patient population, about 86% of children suffer from respiratory diseases and digestive diseases, and there is a huge demand in them. However, among the more than 4,000 domestic pharmaceutical factories, there are only more than 10 companies specializing in the production of children's medicines, and there are only more than 30 companies producing children's medicines. But it cannot be said that such a large market has been abandoned by companies. In fact, many existing medicines in China are marked with a reminder that children’s medication should be reduced in their instructions. Pediatricians in Chinese hospitals will prescribe appropriate doses based on the child’s age and weight. . However, there is a lack of special dosage forms and specifications for pediatrics. At present, several professional pediatric drug manufacturers in China are also leading the development of child-friendly dosage forms. However, children are a group of special drug users who have high requirements for the clinical safety of drugs. However, relatively weak clinical research capabilities have always been a common problem of domestic companies. The development of clinical research on children's drugs has problems in recruiting subjects and high safety risks. Because of the balance of risk and benefit, companies often enter this "niche" market cautiously.

　　 Foreign countries are leading the country in the development of suitable pediatric dosage forms. For example, the US FDA has paid special attention to the management of pediatric drugs in recent years, and has formulated a series of labeling regulations, requiring manufacturers to provide timely information on the safety of pediatric drugs. The development of new pediatric drugs mainly focuses on clinical safety evaluation, formulation development, and research on new indications. The FDA requires supplementary changes to the drug labeling that can be used for the treatment of pediatric diseases. Policy support for children's medication has already begun to show signs of improvement in the new medical reform stage. For example, for childhood leukemia, the state has a major illness medical insurance system to increase the reimbursement ratio; it has introduced a hierarchical management of antibacterial drugs, which has effectively curbed the problem of pediatric antibiotic abuse; the government has proposed encouraging the development of basic drug formulations for children, and cheap drugs for fixed-point production to ensure supply. It should be said that the current policy is to ensure that children are treated for their illnesses and to emphasize the safe and rational use of medicines for children. In the national major new drug creation project, the research and development of drugs for major diseases of children has also been included in the plan.

We believe that more companies will join the children's drug market in the future. In the future, children's drug manufacturers will be polarized. One is the high-end drug field, mainly for children's rare diseases, genetic diseases, tumors and other difficult-to-treat drugs. The development of medicines for diseases; one is a new drug release system research and development company, mainly for children’s antibacterial drugs (mainly cephalosporins and macrolides), children’s chronic diseases (asthma, diabetes), and children with high incidence (colds, Cough, dyspepsia, etc.) development of special pediatric dosage forms for drugs. There is also our traditional Chinese medicine. In the minds of most parents, it is safer than chemical medicines, such as the varieties of Chinese medicines that clear away heat and reduce inflammation, invigorate the spleen and appetite. However, the development of new formulations of traditional Chinese medicine is lagging. If it can be developed for children, it has a suitable taste. , Chinese medicine type with simple and convenient way to take, I believe the market demand prospect is better.

Let the sun shine into the innovative high wall

　　Reporter: So what needs to be locked in the R&D project? In the crowdsourcing business environment, how can the concepts of complementarity and cooperation penetrate?

Tao Jianhong: It is not difficult for us to feel that ensuring that medicines are safe and effective has risen from the demands of people’s livelihood to national interests. The safety of a country’s medicines has become an important indicator of the soft power of science and technology and the level of national health protection. Security puts forward higher requirements. What new drug R&D needs to lock in is the development of safe and effective drugs, not a risky investment. Respecting common sense, respecting facts, and strictly observing the authenticity and accuracy of research and test data is a basic requirement. New drug development that leaves this point must be stopped as soon as possible, and every pill must enclose the conscience of the industry.

　　 The complementary thinking in R&D embodies flexibility. To put it vividly, it means "people don't have me, people have me better, and people are better than me". Real innovation is unforeseen, unplanned, and even unimaginable, so we should have different models and open opportunities instead of just providing a single path and a single model.

In the past two years, due to the difficulty of original innovation, me-too drugs have the characteristics of strong purpose, low investment, short cycle and high success rate. With competitive strength, me-too drugs will be the best choice for enterprise innovation. For example, Hengrui's Irecoxib is a me-too innovative drug of Celecoxib, and it is a domestically-made "blockbuster" drug with great potential.

Chiral drugs have become a new direction in the pharmaceutical industry. According to statistics, the sales of chiral drugs are increasing at a rate of 6.6% each year, while the racemate drugs are increasing at a rate of 29.5% each year. Among the more than 2,000 drugs commonly used in my country There are more than 600 types of chiral drugs, but there are less than 100 active single enantiomers, accounting for less than 20% of the total number of chiral drugs, which is far below the global average. The 1.5-time development of chiral mixed drug modification has become a national strategy for drug development in my country.

　　The huge research and development costs of new molecular entities have discouraged many manufacturers. The new use of old drugs has many advantages. For example, the research and development process can avoid the existing toxicological and pharmacokinetic evaluation, so it can greatly shorten the development time and research and development costs (about 40%), etc., so that many pharmaceutical manufacturers Eager to try. The new use of old drugs is mainly reflected in the application of new preparation delivery systems and the continuous expansion of product indications. It is typical to develop existing drugs into new pharmaceutical preparations. Approximately 400 companies around the world are engaged in the research and development of drug delivery systems. New drug delivery systems account for more than 10% of the entire pharmaceutical market. New high-end drug formulations such as sustained-release and controlled-release preparations and targeted preparations are encouraged by my country One of the important areas. For example, in the future, oncology drugs such as microspheres, liposomes, and monoclonal antibodies will shine in the future. By 2015, anti-tumor targeted therapy drugs in the seven major global pharmaceutical markets will exceed US$50 billion, a compound annual growth rate. Up to 11%. In the field of hepatitis medications, the market share of pegylated interferon injections will increase to 12% in the future, while ordinary interferon injections will drop to 1%.

　　In fact, innovation is interdependent. The future innovation of mankind may not be able to distinguish between the East and the West, China and the United States. All innovations must be me in you and you in me.

The team working on new drug research and development is actually more willing to step on the shoulders of others, rather than stepping on the corpses of predecessors. Only with an open and innovative concept can China truly stand on the shoulders of the West in the future, absorb its strengths, and make up for it. So short, go further.

　　 Let efficiency stand on the shoulders of predecessors

　　Reporter: Benefit is the center of all economic activities of an enterprise. Improving the efficiency of R&D is to ensure the benefits. So how to improve the efficiency of R&D?

　　 Tao Jianhong: You are only half right. The improvement of efficiency does not mean the improvement of efficiency. If the direction is wrong, the greater the efficiency, the greater the loss. Therefore, to improve the efficiency of new drug research and development, it is necessary to have some reverse thinking, and it is very important to avoid high-level repetition. The process of independent innovation is easy to fall into the trap of “technology first”, ignoring market demand research and effective management of technology transformation, leading to a disconnect between R&D and marketing. There is a high-level repetition in the field of anti-tumor drugs. There are 6 types of tyrosine kinase inhibitors on the market in my country, all of which are imported products of multinational companies. In the clinical and marketing approval stage, there are 28 varieties from 14 manufacturers, of which category 1.1 new drugs account for 19. The other is a new type of diabetes treatment drug DPP-4 inhibitor (generic name ××liptin). There are 3 foreign-funded varieties that have been marketed in China. In 2012, there were 8 manufacturers, and 9 kinds of drugs with different generic names were being declared. Lieptin products are also an area prone to high levels of duplication. At present, in the development of the antithrombotic drug clopidogrel, there are signs of clustering. Clopidogrel raw materials and preparation products have been declared by 16 manufacturers, and there are 48 raw materials and preparation products of clopidogrel bisulfate. The manufacturer declares.

　　 As for how companies can improve the success rate of new drug research and development?

　　 We suggest starting from 5 aspects:

The first is to comply with the principle of protecting intellectual property rights (entry into the WTO, intellectual property rights, etc.). For example, when establishing a “me-too” new drug or generic drug development project, pay attention to searching drug patents and other documents to avoid worthless repeated research; in the process of developing new drugs Patent protection should be applied for achievements with market prospects, and patent coverage should be as complete as possible.

The second is to actively innovate to extend the upward cycle of patented drugs. It can improve original drugs or change the drug delivery system a few years before the patent expires, or convert it to OTC in the year when the patent expires. It can also increase the number of drugs by improving the route of administration. Safety, extend the trademark life cycle, improve patient compliance, and make compound preparations to extend the product life cycle.

　　 The third is to focus on brand building of generic drugs (focus on market opportunities for first generic drugs).

　　Fourth is to be good at leveraging the power of cooperative R&D institutions.

　　Fifth, it is highly concerned about drug safety and early intervention in drug development. If early judgment can be made in the drug discovery stage, it is expected to significantly reduce drug development costs and later risks.

　　 Another factor directly related to efficiency is time. At present, the R&D investment in my country's pharmaceutical industry accounts for an average of 1% to 2% of sales revenue. However, the R&D intensity of some independent innovative companies has reached more than 7%. Leading companies such as Luye, Hengrui and Simcere have all exceeded 9.4%, close to the proportion of R&D investment of international pharmaceutical giants. Coupled with the increasing state support for independent innovation, the research and development funds for Class 1 new drugs are still guaranteed, and the time cost is still an unbearable burden for enterprises.

From the perspective of the average approval time for a new approval in the past 5 years (from the start of production declaration to the time when the approval is obtained), chemical drugs have increased from 1.6 in 2007 to 2.4 in 2011, and biological products have increased from 1.7 to 2.4. In 2.5 years, proprietary Chinese medicines rose from 2 years to 4.7 years. It takes longer to approve a new class 1 chemical or biological agent, and it takes 4 years at the longest. Will such a long waiting time miss the golden opportunity for the drug to go on sale, and have to raise a question mark? Therefore, the development of new drugs nowadays is not about being unable to invest, but not being able to wait.

Compared with foreign countries, the FDA issued the "Prescription Drug Applicant Pays Act (PDUFA)" in the early years to accelerate research and development. During the five years from 1992 to 1997, PDUFA achieved great success. The FDA did not lower the review standards for new drugs and increase the number of countries Under the premise of financial appropriation, the piles of drug applications have been processed, new approval mechanisms and processes have been explored, and various work time limits in the drug review process have been established. Although the number of new drug applications increased from 70 in 1993 to 121 in 1997, the average approval time has dropped significantly from 21 months/case before the implementation of PDUFA to 12 months/case at the end of the 1997 fiscal year. In 1997 and 2002, the U.S. Congress successfully passed a five-year postponement of the PDUFA Act. Now that the new five-year (2013-2017) extension will begin again, it can be seen that the mainstream international approval agencies are still trying to shorten the approval time under the premise of ensuring safety. This is worth learning from.

　　 Of course, out of humanitarian requirements, my country has opened a green approval channel for drugs in special periods, such as the H1N1 influenza virus split vaccine, and it only takes less than 1 year to obtain approval. Recently, in response to human infection with H7N9 avian influenza, Peramivir Sodium Chloride Injection, a new anti-influenza drug independently developed by my country, has been approved for accelerated approval. This will be good for new antiviral pharmaceutical companies.

Let the pursuit hold the original romance

　Reporter: While a steady stream of drugs is being produced, the mental dilemma in the development of new drugs will also follow. In your opinion, how should people who pay attention to research and development seek incentives?

　　Tao Jianhong: The four aspects of innovation, lock-in, complementarity and efficiency must be systematically considered in the establishment of new drug research and development projects, or we can call it the "beautiful philosophy" in the establishment of new drug research and development projects. Innovation does not have a perfect end, it needs to move forward gracefully under pressure. Innovation requires external incentives, and people who participate in innovation must continue to motivate themselves. Regarding this point, I would like to say an interesting episode. In the planning of this issue of "Vitality China", everyone has debated the choice of cover image. Careful readers will notice that the snail on the cover image of the planning, It is a very slow-moving animal, and it seems to form a strong contrast with the concept of "vitality". What makes us finally adhere to the aesthetic intuition is the revelation of two fables.

　　 One of the stories says that snails used to have no shells, but he climbed to the heavens and prayed for a shell from the heavens. Why do we have to install a beautiful shell? Hypocrisy or self-deception? The snail pondered for a moment, and solemnly replied: For this one-time life. In the fierce market competition, Chinese companies have not yet been confident to withstand repeated R&D failures, because too much uncertainty has left companies with insufficient determination. In order to innovate this one-time life, let us give new drug research and development better The incubator allows fragile drug innovations to be more protected.

　　 Another story is that after the snail who was good at flying won the championship of the flying competition, he didn't want to make progress and became intoxicated. As a result, his wings degenerated and the trophy became a hard shell, and he could only crawl on the ground. This is a wake-up call, even if you have come a long way on the road of research and development, you must not forget why you started. Please don't think about whether it will succeed. Since we have chosen a far place, we only need to take care of the wind and rain; we only need to be sure, hold on to the original romance, if you lose, you will lose to the pursuit, if you want to win, you will be beautiful.

"The premise of innovative thinking in the development of new drugs is a conjecture about market demand. The market will refute this conjecture one after another. Those who have gone through rounds of market replies, and have been constantly revised and adjusted, eventually survived. It is the innovation that is truly productive."