What is E17 that allows Hengrui, Baekje, and Cinda to launch new drugs at home and abroad and is popular with MNCs in China?

With the increasing globalization of drug research and development, international multi-center clinical trials (MRCT) are becoming a trend

From the traditional innovative drug company Hengrui to the innovative drug companies Baiji, Cinda, Hutchison, etc.

According to the latest data from CDE, as of August 9, 2021, the total number of trials registered on the drug clinical trial registration and information disclosure platform was 14,092, of which 1,141 international multi-center clinical trials, accounting for 8.

Although international multi-center clinical trials are increasingly recognized, there are many difficulties and challenges in launching a global drug research and development project

In order to increase the recognition of international multi-center trials among global regulatory agencies and explore the possibility of registering and approving new drugs on a global scale, the ICH E17 guiding principle came into being, and since its birth, it has become the most important of the E series.

The so-called E17.

Now, nearly two years have passed since China implemented E17.

01 "Global Synchronous Registration" was launched

After the National Medical Products Administration (NMPA) officially became a member of ICH in June 2017, China began to truly integrate into the international drug regulatory system

In the four years since joining ICH, China's drug review reform has achieved great results and at the same time promoted the process of China's drug innovation

One of the most important changes is that China has begun to participate in the simultaneous R&D and registration of global drugs

Clarivate Analytics' data also shows that in 2018, the United States accounted for 68% of the countries where new drugs were launched for the first time in the world, and China only 7%

Data source: Clarivate Analytics

In fact, for a long time before China joined the ICH, it was impossible to achieve simultaneous global drug R&D and marketing

One of the big reasons is the red line drawn by the policy

First, imported drugs can only undergo international multi-center clinical trials in China after entering Phase II abroad; second, imported drugs can be submitted for marketing in China after they are approved for marketing overseas; third, international multi-center clinical trials are not counted as clinical trials.

This policy once allowed the time difference between the overseas market time and the domestic market time of imported new drugs to reach more than 5 years

Although the 2015 "International Multi-center Drug Clinical Trial Guidelines (Trial)" has also cleared many obstacles for China's global R&D and provided useful technical standards for reference, in the eyes of many industry insiders, the guidelines are more It focuses more on the standardization of clinical trials conducted by multinational pharmaceutical companies in China, while the guidance for Chinese local pharmaceutical companies on how to conduct a large-scale international multi-center clinical trial is still slightly insufficient

After NMPA joined the ICH, especially since China began to implement the E17 guidelines, in the early clinical research in China, the dream of formulating international research and development strategies, global simultaneous research and development, and simultaneous registration can finally be realized
.

Among them, Luye Pharma’s risperidone microspheres (II) for injection approved in January 2021, and Trastuzumab for injection approved by Fuhong Hanli in August 2020, all benefited from After NMPA joins ICH, the clinical guidelines are synergistic
.

For multinational pharmaceutical companies, the submission of some of their innovative drugs in China can also be only about 1-4 months later than the United States and the European Union.
Compared with the previous 5 years, the time difference is not big.

.
Many of these drugs can be added to the global confirmatory clinical research, and some have begun to join the early research, including BMS, Boehringer Ingelheim, Novo Nordisk, Takeda, AstraZeneca and other companies have launched similar "China The "Synchronization" plan will fully incorporate China into the global clinical development landscape
.

At the same time, China's international multi-center clinical trials have become increasingly active
.

A set of data can support this change
.

In 2015, domestic companies only carried out clinical trials in 14 overseas countries, with only 48 projects
.
By 2019, Chinese pharmaceutical companies have deployed overseas clinical trials in more than 50 countries, and the total number of cumulative projects has exceeded 340
.
Companies including BeiGene, Hengrui Pharmaceutical, Yasheng Pharmaceutical, Tianjing Biological, Shandong Luye, etc.
have begun to actively deploy international multi-center clinical trials overseas
.

Since the 2020 epidemic, with the development of new crown vaccines and drugs, the choice of clinical trial sites for Chinese pharmaceutical companies has become more and more diversified
.
At the end of 2020, Xu Nanping, deputy minister of the Ministry of Science and Technology, stated that China is cooperating with 16 countries including the UAE and Brazil to carry out international multi-center phase III clinical trials
.

02 Landing problems

The implementation of E17 has promoted the "global new" process of Chinese pharmaceuticals
.

But also because these guiding principles have just been implemented, there are still many running-in and challenges in the implementation process
.

For Chinese pharmaceutical companies, completing an international multi-center test is a comprehensive test
.
Because there are big differences between countries in terms of standard treatment, basic patient treatment, and working habits of the medical system, which test the company's clinical trial management capabilities
.
How to reasonably use E17 guidelines for pharmaceutical companies and implement them in actual research and development has become a difficult point
.

In 2020, in a questionnaire survey on ICH E17, the main problem reported by pharmaceutical companies is the distribution and progress of sample size
.

This is mainly reflected in the uneven distribution of sample size among regions, especially the insufficient development weight in China
.
In fact, in many cases, Chinese patients are usually only enrolled in phase III of an international multicenter clinical trial, and the sample size is limited, which directly leads to inconsistent regional results, or inability to evaluate, and also makes existing research projects Can't keep up with the progress
.

At the same time, this imbalance also reflects another problem, that is, because of China's special requirements on IND declarations, it will cause a time difference of about 7 months for both China and the United States to submit an application to the first patient enrolled in the group at the same time.
This makes it difficult for Chinese patients to join early clinical projects, and it also affects the number of cases joining phase III clinical studies
.

Li Hongmei, senior director of clinical development of Boehringer Ingelheim Greater China Medical Department, once publicly pointed out that China's participation in international multi-center early clinical research and development has three aspects
.

"First, early data on the Chinese population can be obtained to better guide the design and operation of late-stage clinical trials in China; second, Chinese patients can use global innovative drugs as soon as possible.
If drugs are urgently needed in the clinic, early data can be used to support simultaneous global approvals.
If it is a high-incidence disease in China, the global R&D progress of this new drug can be accelerated; third, the weakest part of China’s pharmaceutical industry chain is early stage R&D.
Only by participating in and continuously learning can we establish and improve China’s pharmaceutical R&D industry chain.
, The introduction is truly original, and ultimately promotes the growth of the global pharmaceutical industry
.
"

In addition to sample size, pharmaceutical companies still face a problem when implementing the E17 guiding principles.
Because of the inadequate understanding of the principles, it is difficult to distinguish "ethnic differences" in the early design stage
.
Especially for the specific application of the E5 principle and the E17 principle, there is still confusion
.

In fact, although E17 evolved from the 20-year-old E5 (ethnic factor), it also integrates E5, E6 (clinical trial management practices), E8 (general considerations for clinical research), and E9 (statistics for clinical trials).
Guiding Principles) and other principles, but it is still very different from E5
.

At this year’s DIA conference, CDE experts pointed out that the scope of application of the E17 guidelines is for international multi-center clinical studies that are used to submit drug approval or meet post-marketing requirements.
The main object of discussion is confirmatory clinical trials.
Other stages such as The MRCT of early research and development or later research can refer to E17.
"Unlike the bridging strategy proposed by E5, E17 emphasizes the global consideration as a whole
.
"

In addition to the rules themselves, because the domestic research and development of innovative drugs has just started, all supporting measures are slowly being followed up, which makes it impossible to meet certain specific test requirements in an international multi-center clinical trial
.

There are cases showing that a multinational pharmaceutical company's research on a new Alzheimer drug in China requires the use of PET tracers or cerebrospinal fluid to enroll patients in clinical trials, but these testing methods have not yet been approved for marketing in China.
Will cause obstacles to the advancement of the test
.

This also means that in addition to guiding principles that need to be in line with international standards, related supporting policies and measures also need to keep up with the pace of global simultaneous research and development
.

03 Eight Countermeasures

In order to smooth the global innovation path of Chinese pharmaceutical companies, experts in both CDE, pharmaceutical companies and industry are actively providing ideas and suggestions to make the E17 principle more perfect
.

After summarizing the various suggestions made by regulators and industry insiders at this year's DIA conference, the E-medicine manager summarized them into the following points:

One is that regulatory agencies encourage companies to consider global patients as a whole in international multi-center clinical trials, and include China in the early stages of the plan
.
In fact, Chinese patients can get more and more extensive data by joining Phase I and Phase II clinical studies, and they can also join Phase III clinical studies more quickly
.

Second, in the design of clinical trials, the same global plan should also be considered, and there should be no significant differences
.
This requires the researcher to have a pre-judgment on the impact of the research results, consider in advance and make corresponding preparations
.
Such as genetic, disease standards, treatment stages, non-pharmaceutical interventions and other factors in the population, differences in medical practices such as standard treatment, available drugs and their usage and dosage, and differences in diets and cultures in different regions.
Suggestions Consult experts in each region to comprehensively judge whether the design of clinical trials is feasible
.

The third is in terms of sample size.
The E17 guiding principle usually evaluates the sample size based on whether there is a difference between the patient population and the foreign population and the size of the difference, combined with the overall number of Chinese patients
.
Therefore, in the implementation, specific analysis should be made according to specific conditions such as drug characteristics, population treatment stage or clinical needs, and communicate with regulatory agencies as soon as possible to provide a good precondition for supporting the distribution of sample size through combined populations and combined regions
.

Fourth, in clinical design, both internal factors and external factors must be considered
.
Because internal factors can be found in early clinical trials of drugs, research and development of indications for similar diseases, and preclinical studies
.
However, external factors are often overlooked, such as whether there are differences in the definition of disease in various countries, whether the diagnosis and treatment guidelines are different, etc.
, in many cases, the confirmation of the primary endpoint indicators, the efficacy and safety evaluation standards, etc.
are in different regions or Differences in countries will ultimately affect the results of the research
.

Fifth, when China's data results are consistent with the overall results and the sample size is small, complete evidence is of great value for risk and benefit assessment and listing approval.
When the results are inconsistent, it is critical to systematically analyze to find out the underlying causes
.
In addition, communication with clinicians and understanding of the diagnosis and treatment of the disease under study and unmet needs in China are also crucial
.

Sixth, planning for the implementation and full application of the guidelines, which not only considers how to integrate with international standards as soon as possible, but also considers China's actual national conditions, solicits opinions from pharmaceutical companies, and strengthens communication
.

Seventh, E17 and the entire E series of guiding principles are complementary.
Each guiding principle is not isolated.
In practical applications, they should be put together for comprehensive consideration
.

Eighth, all parties should jointly promote the improvement of the legal process in the international multi-center experiment
.
Including medicine, statistics, clinical pharmacology, regulatory science and other multidisciplinary joint participation and discussion, to promote the continuous improvement of the efficiency of human genetic resources and approval, and to further optimize the registration regulations such as verification, inspection, review process and data requirements
.