Why is it difficult for China to have its first new drug?

**: Intellectuals

Written by |Xu Juncai, former deputy director of Shanghai Pharmaceutical Clinical Research Center

A first-in-class drug (FIC) is a drug that uses a completely new and unique mechanism of action to ** a disease. The successful launch of the first-in-class drug means that it has been proven to have reliable efficacy and a manageable safety profile in clinical trials, and can be approved by drug regulatory authorities in most countries where pharmaceutical companies are streaming (the authors believe that at least three or more countries have been approved by the authorities, including the United States, China, the United Kingdom, Germany, France, Italy, the Netherlands, Switzerland, Denmark, Sweden, Japan, India, etc.). China has wasted a lot of R&D resources on involution and low-level fast imitation, and blindly imitating track varieties is actually facing extremely high risks. The innovation of first-class drugs is not simply the innovation of a single technology, but also involves all aspects of society and the country. It is necessary to improve the national education system, especially basic educationEstablish a system for the state to encourage innovation;Avoid large-scale fake innovation projects;A higher standard of emphasis is placed on the quality of pharmaceutical production.

The windfall profits of first-in-class drugs (FIC) and the hegemony of the United States

Once the first new drug is successfully developed, you can enjoy the right to set the price, and as a result, there are sky-high prices of drugs in the world, and the five most expensive drugs are as follows:

Fierce Pharma's Most Expensive Drugs of 2023 Report Collation.

However, not every first-in-class drug can be profitable. In fact, on the contrary, the approval of most first-in-drug drugs does not mean commercial success. The most expensive drugs in Schedule 1 are all rare disease drugs and are used on specific individual patients**. The number of patients it is suitable for is small, and it is not promotable, and there is not enough audience to pay for it, so commercially, it is impossible to make profits, or even losses.

At present, the drugs that can make money commercially are basically controlled by international pharmaceutical giants. Because they have a monopoly on the entire disease field and have a large sales team, they are large enough to influence the country's health insurance negotiations**. According to the latest news: Merck, a well-known American drugmaker, in its financial report for the third quarter of 2023, its pembrolizumab (trade name: Keytruda, i.e., K drug antineoplastic drug), sales reached 1840.3 billion US dollars, a year-on-year increase of 188%。So far, it has surpassed the former drug king H drug and become the new drug king in 2023. [1]

The pro-drug king is the American drugmaker AbbVie's adalimumab (trade name Humira-Humira is the H drug antibody drug ** rheumatoid arthritis and other immune diseases), and its sales reached 212$3.7 billion. H drug is the legend of commercial success in the pharmaceutical industry: it was 92With sales of $6.5 billion, AbbVie has continued to rank among the top 10 global pharmaceutical companies after officially replacing Pfizer's Lipitor (liptor hypolipidemic drug) for 10 years. [2]

The dream profiteering of the first new drug is the world's pharmaceutical industry, and even affects the country's economic development direction. The huge economic interest stimulus not only intensifies the competition between pharmaceutical companies, but also prompts every economic power to develop biomedicine as an important area of its social development and economic development. To this end, in recent years, in order to develop their biomedical industry, countries have launched corresponding national plans in order to win the competition.

For example, in 2016, the United States formulated and passed the 21st Century ** Act, which established a national policy and legal basis for the future development of biomedicine. In order to maintain the leadership of new drug research and development in the United States, the investment in new drug research and development in the United States is incomparable to that of other countries. The April 2023 JAMA Health Forum article mentioned the contribution of the National Institute of Health (NIH) to the development of new drugs in the United States. From 2010 to 2019, 356 drugs approved by the US FDA were counted, of which 354 were supported by the NIH (99.)4%）。The two unsupported products are (a chelating agent and an osmotic laxative);In the past 10 years, the NIH has spent a total of $187 billion on basic research on drug targets and applied research on products. [3] Therefore, with financial support, the United States is still in the leading position in the world in the field of biomedicine. According to statistics, in 2021, 84 new active substances (NAS) will be listed in the world, a record high, and the United States is the country with the largest number of new drugs on the market, with a total of 72 NAS listed, 44 (more than 60%) have been rated as "first innovative drugs" by the US FDA, and more than half of the NAS (40) have been granted FDA orphan drug designation for rare diseases. [4]

Difficulties in developing first-in-class drugs

Although the first new drug is full of profiteering, it is also a thorny rose, and few laymen know that there is a high risk in its research and development. As early as 2012, some researchers proposed the anti-Moore law of the pharmaceutical industry: that is, according to the data of drug research and development between 1950 and 2010, the number of new drugs approved by the US FDA for every $1 billion invested in drug research and development is decreasing, about half every 9 years (vice versa: about ten years, the rate of nearly doubling of research and development costs is increasing). [5]

According to a report released by the global biotechnology industry organization Bio, Informa Pharma Intelligence and QLS, the average success rate of 9,704 drug development projects approved by the FDA in the decade from 2011 to 2020 was about 79%。

In April 2023, the JAMA Health Forum mentioned that the NIH has spent an average of $2,956,000 on a successful target.

A first-in-class drug is often based on a new medical discovery or theory. In order to prove this new biomedical theory, it often takes years or decades to verify its basic research and clinical trial validation. After the tested theory is established, it is a process of exploration to implement the production of high-standard products with controllable quality, determined efficacy, and few. After that, the product is reviewed and approved by experts from the drug regulatory agency in the country where it is located. Therefore, the emergence of a successful case is often part of the new exploration in this field. Some of the inventors of the first new drugs in human history have successfully won the Nobel Prize in Medicine.

Penicillin, PD-1, mRNA vaccine, artemisin, ......Several of the great first-of-its-kind drug discoveries in history have gone through great hardships, with the ups and downs of personal opportunities or the dedication of national efforts, and it often takes as long as 20 years from the initial scientific discovery to the final use to treat patients. The success of the research and development of this epoch-making first-in-class drug can have an epoch-making impact on human health, but they are full of various uncontrollable, and people's pursuit of the first new drug is a little helpless: "innovation is not the product of logical thought, even though the final product is tied to a logical structure" A foreign expert explained the mystery. The translation means: "Innovation does not come from logical thinking, although the final product depends on a logical structure." ”

As the American philosopher William James summed it up: "Every discovery goes through three stages: when it was first published, it was thought to be incorrect." Soon after, when the facts were so obvious that they could no longer deny them, they decided it didn't matter. After that, if its importance becomes obvious enough, people will say that it is not a new discovery anyway. ”

The world competition of the first new drug is the worry of Chinese players

At present, among China's innovative drugs, the classification of industry consensus can be as follows:

1) First-in-class drugs, rare, artemisinin counts as one, or has not been available in recent decades;

2) Best-in-class, extremely rare, optimistic BeiGene's zanubrutinib, Nanjing's legendary cilta-cel can be counted as such;

3) Optimize imitation (me-better), also less;Fair view: BeiGene's zanubrutinib, Nanjing's legendary CAR-T product "cilta-cel" can be counted as such;

4) Fast follow, most of the domestic innovations belong to this category, which has become the hardest hit area of involution.

5) There are many small enterprises in China, and most industry experts believe that the imitation level of these pharmaceutical companies is far from the standards of international companies, and the quality of the products produced is worrying.

To sum up, China's current problem is to do relatively low-level innovative drug research and development.

At present, the cost of clinical trials of new drugs has increased significantly, taking tumor clinical trials as an example: the cost of completing a phase I clinical trial of a patient is only directly spent on the research cost of hospitals at the level of 200,000 yuan to 300,000 yuan;Due to the competition for enrolling cancer patients, cancer patients are now the most scarce resource in clinical research. Nowadays, the market has reached a crazy level: the referral recruitment fee for 1 qualified cancer patient can be speculated to 4-50,000 yuan or more;The cost of completing the phase III clinical trial of one cancer patient is generally more than 300,000 yuan. In a similar situation, in the field of rare disease research, many R&D pharmaceutical companies believe that rare disease innovation applications can be quickly approved by regulatory agencies, and everyone is in the same industry to form involution competition, and as a result, the clinical trial costs of some rare diseases also reach hundreds of thousands of yuan.

Without the foundation of first-in-class drugs, too much follow-up will affect the reputation of China's innovation, and at the same time face unpredictable risks.

Due to the lack of basic innovation in our own roots, most of the scientists of innovative drugs are people who have studied overseas and worked in multinational pharmaceutical companies for many years, so too many imitation innovations with the same target often cause foreign experts to misunderstand and think that Chinese scholars are suspected of plagiarizing patents. In the past few years, there have been several cases of Chinese scientists being sued by Big Pharma.

Even though BeiGene's zanubrutinib has full patent rights, on June 13, 2023, Abbvie's Pharmacyclics filed a lawsuit in Delaware District Court, alleging that the drug infringes its US11672803 patent. As soon as the news came out, the share prices of BeiGene's A shares and H shares exceeded 10% significantly, and the case is still in litigation. [7]

In addition, because it is a race track, the wind and grass in the market will bring about a completely huge change in the market, and some innovative drug varieties in China have recently been returned by international sellers. For example, in September 2015, Hengrui Pharmaceutical had a total transaction value of 7The US$700 million overseas rights and interests of its PD-1 antibody SHR-1210 (camrelizumab) were granted to Incyte, realizing the first overseas authorization of an innovative biologics in China, which was terminated by Incyte in 2018. Previously, I-Mab's CD47 was "returned" by AbbVie. On January 11, 2021, BeiGene's tislelizumab to Novartis authorized totaling more than $2.2 billion, with an upfront payment of $6US$500 million, setting a new record for the total transaction volume and down payment of innovative drugs in China over the years. But in 2023, Novartis has returned its rights. So far in 2023, a number of domestic innovative drug pipelines have been returned. [8]

The actual risk of imitating the track varieties is extremely high, and the author experienced it in India's Nanxin Pharmaceutical (Ranbaxy) between 1997 and 1999. At that time, Pfizer developed a quinolone product called ***: trovafloxacin (trovafloxacin), which has the potential to become a blockbuster product, and this product Pfizer successfully developed and was approved by the FDA in 1998, however, the toxicity of the drug only showed itself after the product was marketed, especially its liver toxicity, as a result, several patients died, and the FDA terminated its marketing after timely discovery. As a result, many domestic and foreign companies that are making imitations of their patented products have lost their investment.

In fact, the risk of first-in-class drugs is extremely high, and many unaware risks are only exposed after they are marketed. On December 6, 2023, the U.S. FDA issued an announcement stating that it is investigating whether CAR-T cells** can cause lymphoma (a type of blood cancer) in rare cases. As soon as the news came out, the entire cell industry was in crisis. Due to the requirements of FDA supervision, several clinical trials conducted in the United States by CARsgen in the Hong Kong stock market were required to be suspended, and as a result, its stock price suffered a heavy fall on the 13th, falling by more than 35% intraday as of ***304%。[9]

The approval of first-in-class drugs is a challenge of international scientific competition

Whether or not to approve a first-in-class drug is a very scientifically challenging decision for each country's drug review and approval agency. It requires that the country's drug review and approval experts must have the most cutting-edge scientific knowledge and judgment in the world, and the expert group must have various scientific indicators and processes for review and approval to approve or reject the marketing application of the product. The approval process should even be open and transparent around the world. Let the applicant accept the result of the assessment with confidence. At the same time, let other peers in the world know the fairness and science of the judgment live. At present, the approval process of this first-of-its-kind new drug has become a live broadcast of the trial of the major events of the human century.

Nowadays, there are not many countries that can do such review and approval, and the FDA is one of them, so this is why the United States can launch many new drugs, because most countries have recognized that the FDA's approval process is trustworthy. It is also for this reason that any first-in-class drug has not been approved by the US FDA and is basically not eligible to be a first-in-class drug.

In order for our country to become the world's first new drug army, the construction of China's drug review and approval agency has a long way to go.

After 40 years of hard work, China's economy has taken off so much, but we have rarely approved the first new drug. There have been two first-in-class drug approvals, and the results have caused a lot of controversy.

The first case was in 2003, when the National Medical Products Administration approved the recombinant human p53 adenovirus injection, which was recombined from the normal human tumor suppressor gene p53 and the modified adenovirus type 5 gene. After the approval, it attracted wide attention around the world and was hailed as "a new milestone in the field of genetic research and biological high technology." [10]

However, it was also at that time that there were problems in the clinical trials of several similar products in the world, and the United States and France successively stopped the research and development of such products under development. Such approval capabilities led to international criticism of the management level of China's drug administration at that time. The quality of clinical trials and the approval standards of drug supervision have been questioned by the internationally renowned academic journals Science and Nature Biotechnology. [11，12]

The second case is that in November 2019, the State Food and Drug Administration approved the conditional marketing of mannute sodium (**971) for patients with mild to moderate Alzheimer's disease (AD), which is the first original innovative drug for AD in China. As soon as the news of the approval came out, there were many doubts at home and abroad. Rao Yi attracted the most attention. To this end, on July 6, 2020, Rao Yi published in the journal Cell Research that he questioned all the research articles published by Geng Meiyu, the inventor of the 971 drug, and his team on **971. On July 14, 2020, Professor Rao Yi published "Commenting on Geng Meiyu et al.'s Reply to **971" on his ***, once again refuting the mechanism of action of **971.

For this reason, Geng Meiyu sued Professor Rao Yi for defamation infringement. As a result, in December 2021, the first-instance trial rejected plaintiff Geng Meiyu's claim, saying that Rao Yi's challenge was a controversy in the field of science, encouraging the truth to become clearer and clearer. In July 2023, the Shanghai No. 1 Intermediate People's Court rejected Geng's appeal again and upheld the original verdict. [13,14]

The level of the referee determines the excitement of the game, as well as the scientific, fair and fair. In particular, the approval of a first-in-class new drug is related to the life and health of the public. The establishment of a review and approval agency with international standards that can undertake the protection of Chinese people's health is also an important part of our country's innovation and development.

The author believes that China's first innovative drug is the beginning. We must be cautious about all kinds of first-in-class drugs, and actively participate in the wave of competition for world innovation with a scientific spirit of awe. As workers involved in the profession of first-in-class new drugs, we are faced with various scientific experiments, and each research record and trial process must be written in a timely and truthful manner.

Encourage all first-in-class drug peers!

The author is in awe of all FIC new drug workers: "The research work of the scientists who first innovated drugs is like astronauts in a spaceship, flying to the moon or Mars thousands of miles away, to explore the panacea for human health." Every FLC voyage is full of various risks and uncertainties, and it is hoped that investors, FIC participants, must deeply understand the difficulties in the FIC journey, and only by understanding each other, respecting the interests of each party, working together, and cooperating well, can the FLC voyage be a complete and successful cruise.

I would like to thank Wan Ming and Kevin Xu for their help and support in literature query and article text review in the author's writing.

Note: References omitted.