Data Interpretation: A 10-year Landscape of Innovative Drug Development in China

Data Interpretation: A 10-year Landscape of Innovative Drug Development in China

The new round of drug regulatory system reform launched in 2015 can be regarded as a watershed for the development of China's pharmaceutical industry. Whether from objective data statistical analysis or subjective perception, the industry can witness the tremendous changes in China's pharmaceutical industry. Especially in the field of innovative drug research and development, the changes in the drug supply side are evident. Not only has the number of projects and clinical trials increased significantly, but the innovation of targets, the diversity of drug forms and technologies are also incomparable to before the reform.

If we extend the time to the longer dimension of 10 years, we can better feel the upgrading and advancement of China's innovative pharmaceutical industry. This article is based on the annual report of the National Food and Drug Administration, public data articles, and the research and analysis report of the Medical Rubik's Cube. It summarizes and analyzes the macro changes and trends of innovative drugs in China in the past 10 years (note: differences in statistical time from different institutions may lead to data fluctuations) for reference.

The number of IND applications has increased sharply, while NDA applications have steadily increased

In 2010, only about 30 Chinese innovative drugs were first submitted for IND, and this number has increased to over 640 by 2021. It is not difficult to see from the figure below that after the launch of the pharmaceutical reform in 2015, the number of IND applications for innovative drugs began to increase with the gradual clarification of incentive policies. In 2017, there was a significant turning point of growth, and the number of applications for domestically produced innovative drugs increased significantly.

From the perspective of the types of drugs submitted for IND for the first time, the proportion of chemical small molecule drugs is still relatively high, exceeding 50% in the past 10 years. However, the overall trend has slightly decreased, mainly due to domestic enterprises keeping up with the international forefront in cutting-edge therapies such as cell therapy, gene therapy, and small nucleic acid drugs, maintaining a high popularity, indirectly reducing the proportion of chemical small molecule drugs. It is worth noting that domestic companies began to apply for cell therapy in 2017, and there was an explosive growth the following year. However, in 2019, the number of applications for cell therapy decreased by nearly half.

With the continuous increase of IND applications for innovative drugs, the number of new drugs entering the clinical stage has also significantly increased. Data shows that the number of registered clinical trials has grown rapidly since 2016, especially in 2021 when the total number of registered clinical trials reached 1490, a year-on-year increase of nearly 50%. From the experimental stage, both the total number and the number of new applications per year account for half of the proportion of Phase I clinical studies.

With the passage of time, more and more innovative drug projects in China are being promoted to Phase III and later stages of application and listing, gradually entering the harvest period. From the data, it can be seen that the number of drugs entering the Phase III clinical stage has been continuously increasing in recent years, accounting for about 30%. At the same time, the number of core clinical trials (drug clinical trials aimed at market application) carried out by innovative drugs in China has entered a rapid growth stage since 2016, especially in the field of oncology, where the number of new core clinical trials has exceeded that of American pharmaceutical companies.

In terms of market approval for innovative drugs, NMPA received a total of 101 NDA applications for innovative drug projects between 2010 and 2020, of which 58 innovative drugs were approved. In recent years, the number of NDAs submitted and approved is steadily increasing. Especially after the pharmaceutical reform, the number of approved innovative drugs in China has increased significantly.
 

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; From the perspective of drug types, it includes 38 chemical drugs, 33 biological drugs (including antibodies, recombinant proteins, ADCs, vaccines, cell therapies, allergens), and 12 traditional Chinese medicine varieties.

It is not difficult to see that after the reform of the drug regulatory system, the number of drugs in each stage is showing an increasing trend. Not only are the innovative forms of drugs more diverse and the products covering multiple technological routes, but the field of diseases is also constantly expanding. Under the adjustment of relevant policies, the enthusiasm of enterprises for rare diseases and clinically urgently needed drugs continues to increase, and the time to market domestically and internationally is gradually shortened. In addition, actively exploring innovative drug payments and medical insurance has greatly improved the accessibility of innovative drugs in China.

Approval efficiency accelerates, time window disappears

The goals of China's new round of drug regulatory system reform also include improving evaluation efficiency, accelerating evaluation speed, and shortening the lag of new drug launch time. Data shows that after the reform (July 2015 – December 2020), the IND approval time was shortened by 414 days (87 vs 501 days) compared to before the reform (January 2010 – June 2015), and the approval time for listing applications (NDAs) was shortened by 441 days (483 vs 924 days).

With the adjustment of the approval process for drug clinical trials to an implied licensing system, the review speed has significantly accelerated. However, in terms of the duration of the entire clinical trial phase, it did not bring positive results. According to CDE data, after the pharmaceutical reform, the time from IND approval to the first participant participating in clinical trials increased by 59 days (328 days vs. 269 days) compared to before the reform. Improving the efficiency of clinical trials is an important reform direction in China to encourage innovation, but this process will be influenced by multiple factors such as ethical review efficiency, researcher experience, and clinical trial resources.

The duration of approval for innovative drugs from 2010 to 2020 (source: Nature Reviews Drug Discovery)

The adjustment of the approval process for drug clinical trials to an implied licensing system does not mean that all drug IND applications can be approved. According to CDE data, out of 1466 approved initial INDs between 2010 and 2020, 96% were approved and 4% were rejected. The main reasons for rejection include lack of research information after application, communication difficulties, unreasonable drug clinical benefit risk ratio, and violation of basic principles of clinical diagnosis. However, the proportion of disapprovals is relatively small, which also shows that the level of innovative drug development in China has been greatly improved.

This trend is not only reflected in the number of IND applications and approval rates, but also in the success rate of clinical trials. The overall Phase I success rate of drugs (n=413) that entered initial human clinical trials between January 1, 2012 and December 31, 2020 was 83%, which is higher than the reported historical Phase I success rate (68.9%) and also higher than the global success rate (48.8%) from 2011 to 2020. However, the high success rate of Phase I clinical trials in China may be due to insufficient or delayed reporting of failed Phase I projects, which is particularly common among Chinese pharmaceutical companies.

In the NDA stage, thanks to the implementation of a series of acceleration measures such as priority review, conditional approval, and allowing for accelerated approval based on experimental data from other countries/regions, Chinese innovative drugs are accelerating the shortening of the time window with the world. Compared with conventional approved drugs, the priority review channel and the clinically urgently needed drug channel significantly shorten the review time for imported drugs from China (the time difference is defined as the interval between obtaining new drug approval from the US FDA and obtaining NMPA approval from China, with median values of 19.4 vs 12.2 vs 6.4 months, respectively). In addition, in the past decade, the development and registration strategy of imported drugs in China has shifted from "obtaining approval overseas before conducting domestic bridging research" to "joining multi center clinical trials before global approval", and exempting Chinese clinical trials (usually applicable to clinically urgently needed products already listed overseas) without potential racial differences.

Inspired by these policy changes, the gap in the time to market of 43 imported cancer drugs approved by China between 2010 and 2020 has significantly shortened compared to the United States. For example, the median lag time for the US and China market of imported cancer drugs approved in the US from 2006 to 2010 was 8.7 years, while the lag time for approved cancer drugs in the US from 2016 to 2020 was only 2.7 years.

 

In fact, with the gradual improvement of regulatory systems and the improvement of approval efficiency, the gap between the speed of routine approval and the time limit for priority evaluation has gradually narrowed in recent years. Especially in 2021, the speed of routine approval has shown a trend of surpassing priority evaluation.

The improvement of approval efficiency has also prompted regulatory agencies to take the lead in approving multiple first in class (FIC) drugs globally. FibroGen developed the HIF-PH inhibitor roxadustat, and China was the first country to globally approve its listing; The mannate sodium capsule developed by Ocean University of China, Chinese Academy of Sciences Shanghai Institute of Materia Medica and Shanghai Green Valley Pharmaceutical Co., Ltd. was also the first to be approved in China. However, in the 66 initial NDA reviews completed between 2010 and 2020, 12% of drugs were still rejected due to significant flaws in drug or clinical study design, inconsistent study samples used at different development stages, and inaccurate clinical trial data discovered during the examination.

Undoubtedly, regulatory system reform has greatly promoted the improvement of approval efficiency, shortened the time gap between Chinese innovative drugs and global approvals, and also promoted the gradual improvement of regulatory level. However, there is not much public interaction between regulatory agencies and the industry and scientific community. Apart from soliciting opinions, more emphasis is placed on closed door interactions such as expert consultants and applicant meetings. There has not yet been a meeting system similar to the FDA ODAC, nor has there been any inquiry and interaction in response to major concerns about the launch of new drugs such as Ganlotte sodium.

The advantages of top enterprises are obvious, but challenges still exist

The vigorous development of innovative drugs in China cannot be separated from the active participation of local enterprises. In the past decade, a total of 436 innovative drug products have submitted NDAs in China. Although imported drugs still account for the majority, domestic drugs have significantly increased since 2018. In 2021, a total of 25 domestically produced innovative drugs were approved by NMPA. At the same time, Chinese companies are gradually entering the harvest period for their license in products, becoming an important component of NDA submissions in China in recent years. In 2021, there were 24 license in products submitted in China, accounting for 31%.

The development model of innovative drugs in China is also undergoing changes, shifting from me-too (defined as drugs with the same target and similar mechanism of action as approved drugs) to first in class (defined as drugs that have not yet been approved for the same target or have a completely new mechanism of action). Taking the field of cancer as an example, as of January 2020, there were a total of 821 anti-cancer candidate drugs in different clinical development stages in China, including 404 me too/me best and 359 FIC drugs, with FIC drugs accounting for 43.7%.

Of course, this trend shift cannot be generalized, as there is still a lack of truly global innovative drugs for Chinese innovative drugs. FIC may lead to the emergence of multi target drugs in the small molecule field due to differences in kinase selectivity, thereby improving FIC drug data; In the field of antibodies, with technological progress, the combination of dual target and multi target antibodies has also increased the number of FIC drugs to a certain extent. However, it is also a fact that the proportion of innovative drugs with advanced technology is constantly increasing.

Overall, China is still in the stage of rapid follow-up and gradual innovation, with the effects of leading enterprises gradually emerging. In the past decade, the top 50 pharmaceutical companies (groups) in China have applied for a total of 1160 new drugs, accounting for an overall proportion of 47%. Hengrui Pharmaceuticals has applied for 90 new drugs with outstanding advantages in quantity.

With the active capital market, Chinese start-up pharmaceutical companies are growing rapidly, and a large number of their drugs have entered the clinical stage. In the past 10 years, a total of 689 Chinese companies have completed clinical applications for initial new drugs.

However, for the sake of commercial survival and development, many innovative drug companies in China have chosen me too or fast flow drugs with lower risks and faster research and development speed, including cell therapies that closely follow the international forefront. This strategy has directly caused new problems to a certain extent.

The most direct issue is that China's innovative drugs exhibit severe target duplication and indication overlap. The most abundant types of me-too drugs include CAR-T cell therapy targeting CD19, targeted therapy targeting EGFR or HER2, and PD-1/PD-L1 monoclonal antibodies.

Cancer occupies more resources for the development of innovative drugs in China. As of July 2021, the number of anti-cancer drugs under research alone has reached 1283, with growth mainly driven by immunooncology (IO) drugs (281) and targeted (180) drugs. Among different categories of IO drugs, cell therapy has seen a significant increase, with 144 new active drugs added to the pipeline, followed by T cell targeted immune modulators.

Nevertheless, innovative pharmaceutical companies in China can still explore and utilize accelerated policies to achieve rapid listing. In the field of immunooncology (IO) drugs, PD-1/L1 has approved 14 drugs domestically, of which 5 drugs have been approved after 2021. Multiple drugs have adopted differences in indications to achieve rapid market launch. Overall, almost all Chinese companies have unanimously chosen "rare" and "seriously life-threatening" indications to achieve rapid approval for market launch, including the EGFR T790M targeted drug field. Three drugs have been approved domestically, and five drugs continue to be approved for market launch under the attached conditions.

The dynamic pattern of innovative candidate drugs in China is increasingly giving rise to listed products. However, low-quality and repetitive drug development can affect the enthusiasm of the entire industry. A large number of homogeneous clinical studies will also compete for clinical resources of truly innovative drugs. How to actively and effectively guide the positive development of the industry, promote the development of sustainable innovative therapies, protect patients, and meet clinical needs still requires the continued efforts of all practitioners.