Dr. Sun He is Vice President of Tasly."Compound Danshen Dripping Pills," the international head. He was also the first person to enter the FDA in the Chinese medical profession in mainland China, and he achieved clinical measurement pharmacology in the FDA. The highest level of chief scientist and chief judge. Recently, Sun He came to Suzhou Biological Medicine Industrial Park (BioBAY), to the park dozens of companies doing new drug research and development shared his industry thinking for nearly 30 years. Pharmcube had a Meeting with Sun He after the meeting.
I didn’t do PPT, because according to past experience, how much will last in the PPT I became a PPT, so I will talk to you. If there is any problem in the middle, please feel free to interrupt me. "Sun He's opening seems to be somewhat different. After a brief introduction, Sun He began to speak. The first is how enterprises should do new drugs. Secondly, how to go to the United States and go global. Finally, how products are sold in the European and American markets.
Sun He, Vice President of Shili
Provides the R&D concept of “Product Manual”
In the whole medical innovation layout, Chinese medicine (botanical medicine) It has always been a leader in the world, and China has not done so well in China. In terms of chemical drugs, China is relatively backward. We can only be a follower. People started up a hundred years ago. At the beginning of the year, this is far behind, and the level of experience of personnel is different. Biopharmaceuticals are basically synchronized with China and abroad, and there are not too many differences. Sun He said that China’s new drug research and development can use his “ "Three-run theory" to describe, that is, "chemical drugs are running with others, biological drugs are running side by side, botanical drugs are leading the way."
After the drug is listed, it is still a commodity, if it is Building a building, you must first have a construction drawing. However, many pharmaceutical entrepreneurial enterprises are almost one step by step. "Sun He pointed out that "there are very few companies that have written the product specifications in advance, and then follow the instructions. Solve the problem solved one by one." p>
Sun He believes that the product specification not only includes the product specifications. Route of administration. Indication design. The highest tolerated dose and other research and development content, and even with the subsequent product life cycle management. Physiology data and commercialization content such as sales channels in different countries.
In the development stage, Sun He prefers the concept of “first driver, then car and map”. After summing up the development rules of the US major pharmaceutical companies, he found that few companies first spent a lot of money to “buy a good car” and then wondered who to open. Most of them found a good driver, then went to buy maps and cars, good drivers. Under the leadership, almost no detours can reach the destination. In Sun He's view, even a very promising project, if there is no good project manager, it is difficult to promote smoothly.
The project personnel should be good at "counting"
Sun He also pointed out that usually everyone will be "confusing" by a phenomenon. It is often that a consulting company will release some data. Said that "a new drug for listing will take XX years on average, costing XX funds, investing The rate of report is only XX%..." According to his past experience, the cost and time of different drug developments are very different.
In his view, although clinical trial failures are inevitable, some research and development costs It can still be predicted in advance. For a clinical trial designer, the design of the trial program will not only affect the success or failure of the trial, but also affect the research funding. Sun He said that people in the clinical project of pharmaceutical companies must be "counted". /p>
He takes chemical medicine as an example. Currently, it is recognized that about 10,000 products can be obtained from 10,000 candidate molecules. The failure rate of phase II is 30%, and the clinical failure of phase III is 50%. % of research and development costs are in pre-clinical, 70% of research and development costs are in clinical trials. If it is to develop antibiotics, the general clinical trial will not exceed 5 to 7 days, the research and development costs will be much lower, and if it is the kind of clinical use frequency is more Not only is the clinical cost high, according to the FDA, the new drug is used more than 28 days in a year, and it needs to be a full set of long-term poison, which is also a fee.
Specific to clinical trial fees, in the United States, clinical expenses Including medication follow-up Calculation. Every time involved in basic examination costs, doctor interview fees, ECG costs. From the current general situation, the development cost of an anticancer drug in a test cycle is about 300,000 US dollars / person. High blood pressure, cardiovascular and other chronic diseases 30,000 to 40,000 US dollars / person. The cold is about 20,000 to 30,000 US dollars / person. Enterprises should be prepared, reasonable planning, and reasonable financing before conducting clinical trials.
To have Global Vision
One of the biggest features of new drug research and development is that it is highly regulated by the government. Any other industry is not regulated by the government as much as the pharmaceutical industry.” Sun He said frankly, “Doing new drug development, Be sure to have a forward-looking vision and a globalized landscape."
Sun He said that any pharmaceutical company is developing products, not only to understand who developed it, but also to figure out who is Potential competitors. In his view, generally do innovative drugs are nothing more than two business models, or transfer the project to a certain stage to obtain service fees and later share. Or just go to the market, he further explained.
He even gives examples If the development of the target drug really takes 12 years, then the standard established by the company should at least be guaranteed not to be eliminated after 12 years, and should have a reasonable estimation of the disease state after 12 years. In the meantime, government regulation will be a lifeline for companies to survive. In Sun He's view, companies should start from the first day of research and development of new drugs, they should aim at the global market, and it is undoubted to ask for the highest standards.
In addition, Sun He also talked about some of the secrets of commercial success. For example, it is recommended to declare the FDA first, learn the FDA's specific requirements on the design of the test plan and test data, and then return to the national drug. The Authority, from "knowing it" to "knowing it", will be much easier. At the same time, he also suggested that companies should be familiar with the US commercial insurance reimbursement system and sales system in advance, which is also conducive to product development.
In Sun He’s view, if domestic innovative drugs are sold overseas, is it to choose an overseas branch to establish a sales team or cooperate with a local pharmaceutical company? These are all considered in advance. In addition, for different products, the sales model will be quite different, the number of teams required, and the structure of the staff are also significantly different. He believes that these problems, pharmaceutical companies must understand and figure out.
Pharmcube: Hello Professor Sun! If you choose again, will the first job choose to go to the FDA? why?
Sun He: After a lapse of more than 20 years, I often sigh. In fact, our choice of international students is nothing more than three paths. Either go to the industry (large pharmaceutical companies or biotechnology companies), or go back to campus. Teaching at a university is either going to a government department like the FDA.
At the time, if you went directly into the industry, the income of the company was much higher than the government. But at the time, the personal feeling was In the United States, those large pharmaceutical companies are basically a line, the production of tubes for tube production, the research and development of tube research and development, and the registration of tube registration. If you go to university, it is to write a topic every day, to declare a topic, to do a project, it seems that you can also predict.
It’s a big deal to work in the government. Almost every day, you can see what the world’s largest companies and the smallest companies are doing. The angle of view is not the same. Re-choice I may still go. In the beginning, if you pay less, you will be less. After all, you can shape a person. But then, medicine is a new industry with different days and months. No matter where you are, you need to keep learning. Even I have With 20 years of accumulation, to this day still while studying development p>
Pharmcube:. You spent so long at the FDA, which feel is worth sharing ideas and learning?
Sun He: At least when I was working at the FDA, the FDA's philosophy was not to regulate, but how to help new drugs get listed as soon as possible. So you work here (FDA), holding taxpayers' money every day. It is to think about how to serve taxpayers and bring some "good medicines" to the market as soon as possible.
Secondly, many of the standards set by the FDA are also considered from a business perspective. For example, the FDA has taken into account the clinical trials of patients when they set the validity of some clinical trial data, and sometimes the drug companies choose a range in order to avoid poor drug performance. For a narrower group, the data does not meet the established standards.
Pharmcube: What do you think is the current problem in the development of innovative pharmaceutical companies in China?
Sun He: My feeling is this. Now I am doing a new drug research and development, and I have completed the preclinical study. Then I finished the clinical phase I, started the second phase, and then the clinical phase III, while doing the dry side. Planning. Many companies may not be very clear about which direction to go in the next step. Basically, few companies like us to build a building, first have a very detailed design, and then add bricks and tiles on this design. ”
In short, there may be very few companies that write the “product specification” of the drug first, and then the manual solves the problem solved one by one. Most of them may be walking on the side. While getting it, at the end, go together and absorb it.
And from a regulatory point of view, the final product is not your substance, the substance is already there before applying for clinical trials. The last product should be you. The product manual. The product manual is well written, can solve a patient's problem (or some patient's problem), can be sold off, the doctor will use it. I feel that the product manual has not been written beforehand. It’s “dull to dry.” Chinese pharmaceutical companies may not have this habit yet, I think we should pay attention to it.
Pharmcube: Can you elaborate on your “three-run theory” and the reality you see? ?
Sun He: The development of chemical drugs in the United States has been at least a hundred years old. We are really developing new drugs for chemical drugs, which started in the last ten to twenty years. So I think chemical drugs R & D, China still needs to continue to learn European and American experience, the possibility of catching up in the short term is not big.
In the case of chemical synthesis, nowadays to visit the big pharmaceutical companies in the United States, their synthesis only needs to be Small radios are sized in containers that are densely packed with small tubes. Researchers only need to operate in different orders (click on different numbers on the display) and introduce the parent compound to harvest different compounds. They are currently About 700 lead compounds can be synthesized every day. As far as I know, there is no enterprise in China that can do this.
On the one hand, there are shortcomings in high-throughput screening technology, and on the other hand, limited development experience. Some experienced engineers can see the probability of the drug from the 2D/3D space on the computer, but he may say that he may Incomplete, this is like a long-term accumulation of experience. Therefore, if domestic chemical drugs are catching up with the United States, it still needs to work hard.
Biopharmaceuticals are relatively better because of biopharmaceuticals more than a decade ago. When China began to appear, China began to take off. Probably from 2003 to 2006, the FDA did not approve an antibody drug. I came back in 2006, when many people asked me what should I do? I told them, if you try biopharmaceuticals. So now the domestic biopharmaceuticals are so hot, there are also some reasons.
Second biomedical work from 0 to 1 is still relatively easy, The body stimulates the production of antibodies, and then tries to do the culture. After the expansion, the candidate is made to have a relatively small toxic side reaction and a clear target. Therefore, once it becomes later, the probability of failure due to toxic side effects is much less in the clinical trial. However, China, the real impact on product development is not the preliminary work, but the production capacity. The development of biosimilars, from 2006 to now more than 10 years, the state has given a lot of special funds for innovation, recently just approved a Biosimilars.
Why haven’t they been made? One of the reasons is that the cost is too high. Why is the cost too high? Either because a little pollution has to be abolished, or because of insufficient raw material production capacity, especially the culture solution and the adjuvant need to be imported. For example, South Korea, their biosimilar fermenters are fermented in tons, and Only one company in Guangdong that can do tons of fermentation in China is an insulin-producing company.
So in the field of bio-pharmaceuticals, from 0 to 1, the work is good, from 1 to 10, and A lot of room for improvement. Originally, when we were making a major national drug special defense reply, many companies answered the work from 0 to 1 and did a good job, but when it came from 1 to 10, how to reduce the cost, some stuck. So share my suggestion, do biopharmaceuticals, don't be blindly optimistic because the work from 0 to 1 is done, the real bottleneck is from 1 to 10.
The last botanical drug, our country It has always been called Chinese medicine. Many people will say that Chinese medicine is definitely the first in the world, because Chinese medicine is only available to you in China. Can other countries not do it? In fact, this is not the case. Let's talk about botanical medicine now. Don't forget that Japan and South Korea are Southeast Asian countries. They already have a large amount of research investment in botanicals, and they have to have a business perspective.
We have statistics for a while ago, and there are 134 botanical drug materials reported to the FDA for clinical trials. There are only 14 products from 12 companies in China. So from the FDA's point of view, our botanicals are at least not German, Japanese, Korean. So aggressively.
Pharmcube: Why do you suggest that new drugs must go public in the US?
Professor Sun He: The United States is the only country in the world that does not price new drugs. They rely solely on companies and insurance companies to bargain. Since product prices can be set by themselves, 90% of the world's innovative drugs will be considered. US listing. Most European countries are government-priced, and Japan is also priced by the government. So, the real first in class products, the return to the US market is relatively high.
Pharmcube: What is the system that companies and insurance can negotiate, and what are the implications for drug developers?
Sun He: Let me take the example of “orphan drug” development. Assume an orphan drug, the insurance company promises to reimburse 1 million US dollars a year. There are 600 such patients in the United States, only one drug It is possible to get a market of 600 million US dollars. As long as such a patient community is established, a group of patients will be organized to participate in clinical trials. The trial is successful, and the patients are passed on and the sales staff are free. So orphan drugs can be developed in the United States. The product must have a market.
So I suggest that if you want to go to the China-US double-report, it is best to familiarize yourself with the US commercial insurance system in advance, and also facilitate the future with the insurance department. Negotiation.
Pharmcube: In addition to reimbursement, is the sales of drugs different from domestic ones?
Sun He: Indeed, the US drug sales system is very different from China. For generic drugs (including biosimilars), it is mainly to sign agreements with the local three major drug suppliers. In addition to the FDA requirements In addition to the various reviews, for suppliers, the most important thing to choose to work with is to see if the other party can guarantee the output (supply), and not to “drop the chain” at a critical time.
For innovative drugs In the United States, there is also a rule that the sales of each product is probably no more than 100 people. According to the GSP regulations, it seems that the meeting time cannot exceed 15 minutes per day. If the time exceeds the constraint time, it will be a foul. Therefore, the new drug is sold in the United States, not like China. A team of thousands of people.
I also have a suggestion that when developing drugs in China, we must consider the distribution of the patient's disease. Is the global disease market consistent? Don't wait until it's been 12 years. After the work is done, the drug is no longer available.
Pharmcube: Why is the US government not willing to price new drugs?
Sun He: At that time, there were people in the United States who had proposed to do state pricing. Just like the UK and Europe, the price of medicine was too high. But this plan was bad after it was put forward. The opposition of the three major groups, the most powerful opposition is the insurance company, the second is against the FDA, the third is against pharmaceutical companies.
The theory of insurance companies is that they summed up The experience of past history found that spending $1 on innovative drugs can solve the unmet needs of the clinic, and then can save the insurance company $8, so they resolutely oppose the pricing of medicine. If the price of medical insurance is lost, the innovation will be lost. After the insurance company's actuaries have calculated, their expenses must be increased, not reduced.
From the perspective of the FDA, they believe that 95% of the new international drug innovations are actually In the United States, if the core willingness to innovate is reduced, the trend of global pharmaceutical innovation will decline. The result of the opposition of the three major groups is that the United States is the world’s new drug product to date. The region priced by the state. This has caused the entire US innovation trend and the willingness to innovate to maintain a high state. This is also an important difference between China and the United States. The return rate of new drugs is relatively high, 95% of the world's new drugs are US Approved.
Pharmcube: You also said that the new drug has been patented and can be easily copied. What measures can extend the product life cycle?
Sun He: For chemical drugs, in order to avoid being copied, it is possible to make certain marks. Now, when you go to the US pharmacy to buy medicine, it is easy to see the mark on the capsule or tablet. At the earliest time, Pfizer made Viagra a "blue diamond-shaped small pill", which gives a strong sense of recognition.
Because the patent for general compounds is 21 years, it is possible to develop it. For more than ten years, the remaining life cycle is not long. Like Viagra, it may wait until the time of listing to apply for the “design” patent. During the appearance patent period, other products cannot imitate its appearance. A way to extend the life cycle. So I suggest that for the export of Chinese original medicines, you should also think of this when designing products.
Pharmcube: What plans or wishes do you have next? ?
Sun He: At present, the domestic translation of the FDA documents are more literal translation, what is the number of the FDA regulations, such as the validity of the bioequivalence (BE) test results is Cmax at 80~ Between 125%. Few people explain why this is the case, and the translation documents are not specified. Even many people do not understand why the FDA requires PK (pharmacokinetics) research? And when can I do it (or not)? To what extent?
If there is opportunity and funding, I would like to organize a group of people to do a comprehensive combo or alternative translation of the FDA research and development guide documents (rather than simply literal translation), I hope that through this work Better help Chinese companies understand why this is the case and how to apply these regulations flexibly.
Pharmcube: Tasly "Composite Danshen Dropping Pills" has been filed for clinical trials in the United States since the end of the last century. Some commentators say the trial failed. Can you share recent progress?
Sun He: We are preparing NDA, we will tell you when there are new results, thank you.