10-year picture of China's innovative drug development

The new round of drug regulatory system reform launched in 2015 can be regarded as a watershed in the development of China's pharmaceutical indust.

If you stretch the time to the longer dimension of 10 years, you will be able to feel the upgrading and advanced road of China's innovative drug indust.

IND filings increased sharply, NDA filings steadily increased

In 2010, there were only about 30 innovative Chinese drugs that submitted IND for the first time, and this number has grown to more than 640 by 202 It is not difficult to see from the figure below that after the start of the drug administration reform in 2015, the number of IND applications for innovative drugs began to increase with the gradual clarification of the incentive polici.

In terms of the types of drugs submitted for the first IND, the proportion of chemical small-molecule drugs is still the highest, exceeding 50% in the past 10 years, but the overall trend is slightly lower, mainly due to domestic companies in cell therapy and gene thera.

With the increasing number of IND applications for innovative drugs, the number of new drugs entering the clinical stage has also increased significant.

With the passage of time, more and more Chinese innovative drug projects have been advanced to Phase III and the later stage of application and listing, and gradually entered the harvest peri.

In terms of marketing approval of innovative drugs, NMPA accepted a total of 101 NDA applications for innovative drug projects from 2010 to 2020, of which 58 innovative drugs were approv.

Annual number of NDA applications for innovative drugs (Source: Nature Reviews Drug Discovery)

Especially in 2021, the number of innovative drugs applied for listing in China reached a new high, reaching 83, including 51 domestic new drugs and 32 imported new drugs; in terms of drug types, 38 chemical drugs, 33 biological drugs (covering Antibody, recombinant protein, ADC, vaccine, cell therapy, allergen products) and 12 varieties of traditional Chinese medici.

It is not difficult to see that after the reform of the drug regulatory system, the number of drugs at all stages is showing an increasing tre.

The approval efficiency is accelerated, and the time window disappears

The goals of the new round of drug regulatory system reform in China also include improving review efficiency, speeding up review speed, and shortening the time lag of new drugs on the mark.

With the adjustment of the approval process for drug clinical trials to an implied license system, the speed of review has been significantly accelerat.

Length of time for innovative drug approvals from 2010 to 2020 (Source: Nature Reviews Drug Discovery)

The adjustment of the approval process for drug clinical trials to the implied license system does not mean that all drug IND applications can be approv.

This trend is not only reflected in the number of IND applications and approval ratios, but also in the success rate of clinical tria.

In the NDA stage, thanks to the implementation of priority review, conditional approval, and a series of accelerated measures that allow accelerated approval based on trial data in other countries/regions, Chinese innovative drugs are accelerating the shortening of the time window with the wor.

Motivated by these policy changes, the time gap between the 43 imported new cancer drugs approved in China from 2010 to 2020 has been significantly shortened compared with the US market, such as the median time to market of imported cancer drugs approved in the US from 2006 to 201 The lag time for oncology drugs approved in the.

2016-2020 The time gap between the approval of new cancer drugs in China and the launch in the United States (Source: Nature Reviews Drug Discovery)

In fact, with the gradual improvement of the regulatory system and the improvement of approval efficiency, the gap between the speed of routine approval and the time limit for priority review has gradually shortened in recent yea.

The improvement in approval efficiency has also prompted regulators to take the lead in approving multiple first in class (FIC) drugs global.

The HIF-PH inhibitor roxadustat (roxadustat) developed by FibroGen, China is the first country in the world to approve its listing; developed by Ocean University of China, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Shanghai Green Valley Pharmaceutical .

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The mannatide sodium capsule was also the first to be approved in Chi.

However, in the 66 first NDA reviews completed from 2010 to 2020, 12% of the drugs were still due to major flaws in drug or clinical research design, inconsistent research samples used in different development stages, and untrue clinical trial data found during the inspections, e.

Reason Denied Approv.

There is no doubt that the reform of the regulatory system has greatly promoted the improvement of approval efficiency, shortened the time difference between Chinese innovative drugs and global approvals, and promoted the gradual improvement of the regulatory lev.

However, regulators have little public interaction with industry and scien.

In addition to soliciting opinions, it is more focused on "closed-door interactions" such as expert advisors and applicant meetin.

There is no meeting system similar to FDA ODAC, and there is no inquiry interaction to respond to the marketing concerns of major new drugs (such as mannatide sodiu.

Leading companies have obvious advantages, but challenges still exist

The vigorous development of innovative drugs in China is inseparable from the active participation of local compani.

In the past ten years, a total of 436 innovative drug products have been submitted for NDA in Chi.

Although imported drugs still account for the majority, domestic drugs have increased significantly since 201 In 2021, a total of 25 domestic innovative drugs have been approved by the NM.

At the same time, the products of the Chinese company License in have gradually entered the harvest period, which has become an important component of the NDA products submitted in China in recent yea.

Among the products submitted for NDA in China in 2021, there are 24 license in products, accounting for 3

China's innovative drug development model is also changing, from me-too (defined as drugs with the same target and similar mechanism of action as already approved drugs) to first-in-class (defined as drugs targeting the same The target has not yet been approved for any type of drug or a drug with a completely new mechanism of actio.

Taking the field of oncology as an example, as of January 2020, there were 821 anti-cancer drug candidates in different clinical development stages in China, including 404 me-too/me-better and 359 FIC drugs, with FIC drugs accounting for 4

Of course, this trend change cannot be generalized, and China's innovative drugs are still insufficient in the true sense of the world's first-in-class dru.

In the field of small molecules, FIC may lead to the emergence of multi-target drugs due to the difference in the selectivity of kinases, thus improving the data of FIC drugs; in the field of antibodies, with the advancement of technology, dual-target and multi-target combination antibodies are also available to a certain exte.

increased the number of FIC dru.

However, it is also a fact that the proportion of innovative drugs based on advanced technology continues to increa.

In general, China is still in the stage of rapid follow-up and incremental innovation, and the effect of leading companies is gradually emergi.

In the past 10 years, China's top 50 IND pharmaceutical companies (groups) have declared a total of 1,160 new drugs, accounting for 47% of the tot.

Hengrui Medicine has declared 90 new drugs, and the number has a leading advanta.

With the active capital market, Chinese start-up pharmaceutical companies have grown rapidly, and a large number of pharmaceutical companies have entered the clinical sta.

In the past 10 years, a total of 689 Chinese companies have completed the clinical application of their first new dru.

However, based on the consideration of commercial survival and development, many innovative drug companies in China have chosen me-too or fast-follow drugs with less risk and faster research and development, including cell therapy that closely follows the international fronti.

This strategy, to a certain extent, directly caused new proble.

The most immediate problem is that China's innovative drugs show serious target duplication and overlapping indicatio.

Among the me-too drugs, the most numerous types include CD19-targeting CAR-T cell therapy, EGFR or HER2-targeting therapy, and PD-1/PD-L1 monoclonal antibodi.

Overview of the development of innovative dru.

a) Main therapeutic areas; b) Drug targe.

Drugs can target a single target or multiple targe.

(Source: Nature Reviews Drug Discovery)

Tumors take up more resources for innovative drug development in Chi.

As of July 2021, the number of anticancer drugs under development alone has reached 1,283, and the growth is mainly driven by immuno-oncology (IO) drugs (281) and targeted (180) dru.

Among the different classes of IO drugs, cell therapy saw the largest increase, with 144 new active drugs added to the pipeline, followed by T cell-targeted immunomodulato.

China's pipeline of anticancer drugs under development (Source: Nature Reviews Drug Discovery)

Even so, China's innovative pharmaceutical companies can still tap the acceleration policy to achieve rapid market laun.

In the field of immuno-oncology (IO) drugs, 14 PD-1/L1 drugs have been approved in China, of which 5 drugs will be approved after 202 Many drugs use different indications to achieve rapid laun.

In general, almost all Chinese companies have chosen "rare" and "serious life-threatening" indications to achieve rapid approval and marketing, including EGFR T790M targeted (Targeted) drugs, and 3 drugs have been approved in China , and 5 drugs continue to be approved for listing with conditional approv.

China's dynamic landscape of innovative drug candidates is increasingly giving rise to marketed produc.

However, low-quality, repetitive drug development can detract from the enthusiasm of the entire indust.

A large number of homogeneous clinical studies will also snatch the clinical resources of truly innovative dru.

How to actively and effectively guide the positive development of the industry, promote the development of durable innovative therapies, protect patients and meet clinical needs, still requires the continued efforts of all practitione.