The first domestic PD-1 will "pass the court" FDA!

The first domestic PD-1 awaiting the FDA announcement is pulling the heartstrings of the entire industry

On February 8, the FDA announced the materials to be discussed at the ODAC meeting on the 10th.

Image source: FDA official website

In short, on the one hand, the focus is still on the Orient-11 trial being conducted only in China, rather than a global multi-center clinical trial, which does not meet the description of the ICH E17 guideline, and the FDA concludes that given the single-country nature, the Orient-11 results are not.

Image source: FDA official website

The only question facing ODAC members at the upcoming ODAC meeting is whether more clinical trials reflecting the U.

According to FDA statistics, there will be at least 25 oncology drug applications in different drug development stages, planned to be submitted or currently under review in the future, based entirely or mainly on clinical data from China

It is worth noting that in the discussion materials of the ODAC meeting published by the FDA, the ICH E17 guideline, which was mentioned 25 times, is of great importance to all companies doing international multi-center clinical research.

01

What exactly is ICH E17?

ICH E17 refers broadly to the general principles for the planning and design of multiregional clinical trials

This principle can be said to be born in response to the trend

As the main areas of innovative drug research and development have expanded from the United States, Europe, and Japan to China and other Asian and Latin American countries, the mode of clinical trials of new drugs has changed, and clinical trials of the same protocol in multiple regions have become a trend.

However, in an international multi-center clinical trial, there are many uncertainties, and different regulatory agencies have not formed a unified regulatory view on the R&D project in advance

Since its inception, E17 has become the most talked-about item in the E-series (Guidelines for Effectiveness) to improve the acceptability of MRCTs in global regulatory submissions

It is not an isolated principle, but evolved from the 20-year-old E5 (ethnic factor), and combines E5, E6 (good practice for clinical trials), E8 (general considerations for clinical research), E9 ( Statistical Guidelines for Clinical Trials)

Before E17, although the aforementioned E-series principles could ensure that clinical trial data are accepted by the review departments of various governments at a minimum, these rules are still fragmented.

In fact, as early as 2007, China's "Measures for the Administration of Drug Registration" once appeared in the "international multi-center clinical trial" statement, and also put forward relevant requirements for the application of international multi-center clinical trials in China

Since 2012, the annual CDE drug review report will summarize the application status of international multi-center clinical trials

In 2015, the "Guidelines for International Multicenter Drug Clinical Trials" issued by CDE provided reference technical standards for international multicenter clinical trials during this period

After 2017, the annual drug review report no longer emphasizes the application of international multi-center clinical trials, because we gradually incorporate international multi-center clinical trials into the scope of routine clinical trials and no longer specialize it
.

In 2019, the State Food and Drug Administration issued an announcement that a number of ICH guidelines, including E17, have been implemented in China.
It can be said that our international multi-center clinical trials are officially in line with international standards
.

After the implementation of E17 in China, many innovative pharmaceutical companies have successfully filed new drug applications around the world under the framework of the E17 guidelines
.
According to data previously released by CDE, as of July 2021, the number of international multi-center trials registered in China has reached 1,126, accounting for about 8.
31% of the total number of clinical trials
.

02

A case exposed the problem?

The E17 guidelines are used for MRCT studies that submit drugs for approval or meet post-marketing requirements.
They are mainly aimed at confirmatory clinical trials, and are more applicable to the global R&D and design of new drugs
.

Different from the bridging of E5, E17 emphasizes that pharmaceutical companies consider global patients as a whole at the beginning of the design, and designers need to consider from a global perspective after analyzing the differences in various regions
.

The implementation of E17 has promoted the "global new" process of Chinese pharmaceuticals
.
However, it must also be acknowledged that there are still many challenges in the international multicenter clinical practice
.

Last year, the failure of an international multi-center Phase 3 clinical trial of a class 1 biological new drug independently developed by a domestic pharmaceutical company was a good case, which to some extent exposed the possible existence of a pharmaceutical company in the planning and design of an international multi-center clinical trial.
all kinds of problems
.

For example, in the design of the clinical trial in this case, no further research has been done on the doses of different ethnic groups
.
Principle E17 states that a primary analytical method for hypothesis testing and assessment of overall efficacy should be planned in a targeted manner so that it is acceptable to all relevant drug regulatory authorities
.
A structured exploratory approach was used to examine and analyze the consistency of drug efficacy across regions and subgroups
.

In this case, there are also problems of uncontrollable quality of clinical trials, such as patients dropping out, lost to follow-up, and poor cooperation with international CROs leading to problems in trial management,
etc.
These are reflected in the E17 guideline, which states that attention to trial design, investigator training, and quality monitoring during the trial will help achieve the consistently high trial quality required for a successful MRCT
.

As well as the recent issue of approval by clinical data from a single country or region, E17 also mentioned that rationally designed and implemented MRCT trials according to this guiding principle can accelerate the global marketing process of new drugs and support the marketing requirements of different regions
.
However, when MRCT is preferred for new drug registration, the potential impact of regional differences on study results and interpretation should be considered
.

A review expert from a regulatory agency once bluntly stated that in general, we want to design the same program globally and do not want to see obvious differences.
The E17 guidelines provide researchers with opportunities to identify regional differences and their potential impact on efficacy and safety.
With reference to the experience, it is hoped that in the process of clinical trial design, researchers and R&D institutions of pharmaceutical companies can consider in advance, make corresponding preparations, and have a pre-judgment process for the impact of research results
.

The aforementioned experts also said that E17 cannot be viewed completely alone.
E17 has two sides, one is the difference, and the other is the consistency
.
At the project level, the division of regions should be considered in advance, whether countries can be merged, and the consideration of subgroup analysis needs to be communicated with regulatory agencies in advance
.
"The sooner you communicate with regulatory agencies, the better it will be for pharmaceutical companies' research and development
.
"

03

How do pharmaceutical companies play with E17?

In order to make the global innovation road of Chinese pharmaceutical companies smoother, both CDEs, pharmaceutical companies and experts in the industry are actively providing ideas and suggestions to make the E17 principle more perfect in China
.

First, regulators encourage companies to consider global patients as a whole in the early stages of an international multicenter clinical trial program
.
In fact, Chinese patients can obtain more and more extensive data by joining Phase I and II clinical trials, and can also join Phase III clinical studies more quickly
.

Second, in the design of clinical trials, the same global program should also be considered, and there should be no significant differences
.
This requires researchers to have a pre-judgment of the impact of the research results, consider it in advance and make corresponding preparations
.
For example, differences in factors such as genetics, disease standards, treatment stages, and non-drug interventions among the population, differences in medical practices such as standard treatment, available drugs, and their usage and dosage, as well as differences in diet and culture in different regions, etc.
Consult with experts in various regions to comprehensively judge whether the design of clinical trials is feasible
.

Third, at the clinical design level, both internal and external factors should be considered
.
Because intrinsic factors can be found in early clinical trials of drugs, in the development of similar disease indications, and in preclinical studies
.
However, external factors are often easily overlooked, such as whether there are differences in the definitions of diseases in various countries, whether there are differences in diagnosis and treatment guidelines, etc.
In many cases, the confirmation of the primary endpoints, and the standards for efficacy and safety evaluation are performed in different regions or regions.
Country differences will ultimately affect the results of the study
.

Fourth, in terms of sample size, the E17 guidelines usually evaluate the sample size based on whether there are differences between the patient population and foreign populations and the size of the difference, combined with the overall number of Chinese patients
.
Therefore, in the implementation, specific analysis should be carried out according to specific conditions such as drug characteristics, population treatment stage or clinical needs, and communication with regulatory agencies should be conducted as soon as possible, so as to provide a good precondition for supporting the allocation of sample size by combining populations and regions
.

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

The implementation of E17 is also inseparable from the regulatory level.
After China gradually integrates into the ICH guideline system, it will become important to systematically evaluate the “compliance” situation
.
Supervision should also track scientific development forward-looking, so that the science of drug supervision itself keeps pace with the times
.