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Why are domestically-made innovative drugs always dystocia? Pre-clinical research: a key link that needs to be made up

2021-03-03
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What happened to the potential targets published in top academic journals?

There is a model that has spread all over the world. On October 1, the discovery of PD-1 mechanism won the Nobel Prize in Physiology or Medicine. What is exciting is that it not only found a way to hit tumor cells, but also used it Tumor immunotherapy drugs such as O drugs and K drugs developed for the theoretical basis have been on the market for a long time, and the approved indications (types of cancer treatment) are still gradually expanding.

Pre-clinical research
Pre-clinical research

If the “potential target” found in basic research is to draw a “circle” on the “map” of life, then the screening of pre-clinical drug compounds and preliminary functional evaluation and verification are based on the circle on this map. Carry out construction from scratch, from 0 to 1.

“The United States, which has a large number of new drug creations, has a mature system for the development of new drugs from 0 to 1.” On October 12, Chen Xiaoguang, a researcher at the Institute of Materia Medica, Chinese Academy of Medical Sciences, told a reporter from Science and Technology Daily that in my country, this system is close to It has just taken shape in a few years.

System and consciousness are tied together

China lacks a 0 to 1 promotion body

“The major U.S. pharmaceutical companies have departments that specialize in collecting the latest scientific research results, and they are proactively and systematically purchased for follow-up development.” Chen Xiaoguang said that the new drug creation chain needs at least 6 majors and roles to reach the stage of development. Clear division of labor: Small and micro enterprises select a large number of possible lead compounds based on basic theories, conduct preliminary research and development, and buy them by large enterprises.

But in our country, this link of the chain is not connected-large pharmaceutical companies do not want to buy, will not buy, dare not buy, small companies that can research and develop and understand the theory almost do not exist, and some small pharmaceutical companies in my country are called “imitation workshops.” More appropriate.

On the other hand, high-level theoretical research is mostly in institutions of higher learning within the system, and for a long time it has been “nested” in laboratories and cannot be exported.

“Foreign small and micro enterprises are mostly run by scientific researchers themselves.” Chen Xiaoguang said, but so far this has only just started in our country.

Nobel Laureate, Professor Brian Kobilka, Stanford University School of Medicine
Nobel Laureate, Professor Brian Kobilka, Stanford University School of Medicine

A comparison can clearly illustrate the gap. In 2017, Nobel Prize winner and Stanford University School of Medicine professor Brian Kobilka came to China to give a lecture. After explaining the molecular mechanism of drug addiction he discovered, he naturally mentioned it. He established a company to screen compounds based on new discoveries and conduct pre-drug development. “My wife is responsible for the company’s affairs, such as negotiating with investors.” Kobilka said, “Operating the company is very hard and the investment is huge. Now we can only achieve a basic balance of payments.”

However, scientists and researchers with faculty positions or institutional identities in our country rarely mention the matter of starting a company by themselves, and often avoid discussing them. When it must be mentioned, the reference is also very “subtle”. For example, some scientists actually It is the founder of the company, but on the business card is the “chief scientist” of the company.

At present, there is a strong wait-and-see atmosphere as to whether scientific and technological personnel run enterprises are in compliance. After the revision and implementation of the Law on Promoting the Transformation of Scientific and Technological Achievements in 2015, the equity of scientific researchers who became shareholders of new enterprises was granted in the form of rewards. As for the depth of scientific research personnel’s entry into the enterprise, authorization is not clear.

In addition, the slow implementation of specific implementation rules and the huge differences in people’s perceptions of scholars and businessmen over the years have also made it seem that there are no driving bodies to promote the creation of new drugs from 0 to 1, and most of them are limited to areas that are first tested.

“At present, the country advocates the establishment of enterprises by scientific researchers, but there are still many implementation rules that need to be connected. If the overall atmosphere changes, small and micro companies doing new drug research and development will appear in large numbers.” Chen Xiaoguang believes that the current situation will continue for at least 5-8 years. It is possible to promote a large number of small and micro pharmaceutical enterprises with original results to embark on the path of clinical development.

Low imitation threshold

Flock to the short, flat and quick “1 to 100”

Compared with generic drugs with low barriers to entry, fewer failures, and short-term stability, the average cycle of new drug research and development is 10-15 years, with an average investment of about US$1 billion. For many years, China’s pharmaceutical industry has been better at copying from 1 to 100. The extraction and application of artemisinin is probably a rare and representative original innovative drug starting from zero before the implementation of the major new drug creation project.

Generic drugs
Generic drugs

Generic drugs have a higher input-output ratio.” Some people in the industry calculated for reporters and completed the development of a new drug precursor. In the end, even if 100 million yuan was sold to a large pharmaceutical company, there were often multiple large companies during this period. The cooperation of the research group consumes a lot of manpower and material resources. And to develop a generic drug, it is very likely that two or three people will be able to make some modifications to the known compounds or excipients in two or three months, and sell the drug company for two to three million yuan. In such a comparison, the latter is simply “fat”.

The tilted “balance” has made many research institutes keen to take on horizontal topics that can make quick money. “Almost use the resources of the country to make money for yourself, and did not carry out original innovation work.” The industry insider said that the project managers have insufficient estimates for the temptation of the market environment and the emergence of similar situations, and the supervision and correction are not timely. , Resulting in the demonstration and leading role of some platforms in the implementation of new drug creation projects.

The subsequent system reforms “drew salaries from the bottom” prevented capital and researchers from rushing to imitate “small repairs and small supplements”.

According to the data, when the drug consistency evaluation (requiring the efficacy of the generic drug to be consistent with the original drug) was implemented in August 2015, more than 20,000 registration applications were queued for review at the Drug Evaluation Center of the State Food and Drug Administration. After implementation, a large number of new drugs applied for rejection. Cao Cai, former deputy director of the Drug Certification Management Center of the State Food and Drug Administration, once said: “They know the drugs they produce, and they know that they cannot pass the consistency evaluation at all.”

“Last year, China joined the ICH (International Conference on Coordination of Technical Requirements for the Registration of Human Drugs), and the drug regulatory system will tend to be internationalized. All clinical trials have to withstand inspections, and the requirements and costs of producing generic drugs have become higher.” Chen Xiaoguang believes , Raising the balance on the side of generic drugs can help resources be rationally allocated between generic drugs and innovative drugs. “The investment in generic drugs has increased, but the value in the future may not be great. Researchers with original results will definitely choose the development of original drugs with better prospects.”

Really original, who doesn’t love?

In October last year, China’s independently developed “recombinant Ebola virus disease vaccine (adenovirus vector)” with completely independent intellectual property rights obtained the new drug certificate. “The Ebola vaccine is only available in my country and the United States. The United States needs to be kept at minus 8 degrees Celsius, and ours does not need it.” In a keynote report, Sang Guowei, an academician of the Chinese Academy of Engineering, said that in recent years, my country’s major product research and development results have been remarkable.

The landing of major scientific research results complements the vigorous development of the biomedical industry, and the “eyes” of large pharmaceutical companies have also been adjusted, from buying relatively mature varieties to being able to intervene at any stage.

CStone’s CEO Jiang Ningjun stated his criteria: on the basis of good data and good druggability, he also hopes to establish a biomarker research and development strategy in the early stage. “For example, PD-1 is effective for these patients, but it may not be effective for others. Individuals are different. If preclinical studies can be accompanied by studies of the accompanying system, we value it more.”

Jiang Ningjun said that he welcomes the drug pioneers extended from papers published in top journals such as Cell and Nature, or who have made oral speeches at important international academic conferences. “These papers may have been judged by many’masters’ during the submission process, and we are willing to learn more about them earlier.”

“When to invest, there is no definite rule.” Jiang Ningjun denied that he would only invest in obtaining clinical license approval documents. Although the earlier the risk, the greater the risk, but he is willing to advance major innovations. “We can provide more rigorous clinical development guidance, and we also have richer experience in bringing it to the market.”

“At present, there are many projects to choose from, but there are not many innovations that have clear mechanisms and solve major problems.” Jiang Ningjun said, hoping to persist in theoretical research during the continued research and development process from 0 to 1. The clearer the drug mechanism, the more it can win market favor and accelerate clinical implementation.

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