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CSCO-CDE session: Antitumor drug involution is in remission | first scene

 Last Update: 2022-12-30
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At present, the research and development of anti-tumor drugs in China is in a period
of vigorous development.
According to the drug clinical trial registration and information disclosure platform, the total number of annual registrations in China exceeded 3,000 for the first time, and the number of new drug clinical trials in 2021 was 2033 compared with 2020 items, an increase of 38%
compared to the number of registrations in 2020.
Among them, the number of clinical trials of anti-tumor drugs accounts for the largest proportion, and the Chinese Society of Clinical Oncology (Chinese Society of) was held not long ago Clinical Oncology, CSCO) Annual Meeting, the National Center for Drug Evaluation (CDE) introduced the latest progress
in the R&D review of oncology drugs in China.

As of the end of October, the number of IND applications for antineoplastic drugs in 2022 reached 871, and the NDA was 63, and the overheating phenomenon of anti-tumor drug applications has been alleviated
.

Yang Zhimin: Review of new anti-tumor drugs in China

Deputy Director of CDE Yang Zhimin

At this year's CSCO-CDE session, Yang Zhimin introduced the review of new anti-tumor drugs in China in 2022
.
In the report, she repeatedly emphasized "Patient needs" and "clinical value-oriented" indicate that CDE's future work will focus on patient-centered guidance industry R&D plans
.

From January 2018 to October 2022, the IND application of anti-tumor drugs increased from 313 in 2018 to 871 in 2022, and the number of IND applications increased year by year, but the increase was stable, accounting for about half of all IND applications, coupled with the CDE issued various oncology drug development guidelines, the threshold for clinical trials continued to increase
.
Compared with last year's PD-1/PD-L1 and other targets, the overheating phenomenon of the current anti-tumor drug IND application has been alleviated
.
Correspondingly, the registration of anti-tumor NDAs has increased year by year, from 56 in 2018 to a peak of 138 last year
.

Among the new anti-tumor drugs launched in 2022, 55 NDAs have been approved, and the most common tumors in China are lung cancer, breast cancer, hematological cancer and thyroid cancer
.
The number of new drugs developed and approved for digestive tract tumors is large, including 2 liver cancer drugs, 5 esophageal cancers, 2 adenocarcinomas of the stomach or gastroesophageal junction, 2 colorectal cancers, 1 cholangiocarcinoma, and 1 pancreatic cancer
.

Yang Zhimin summarized the outstanding characteristics of China's newly approved new anti-tumor drugs in 2021 as follows:

Yang Zhimin also introduced the consideration
of the current hot combination treatment of CDE.
CDE issued the Technical Guidelines for Clinical Trials of Antitumor Drug Combination Therapy on December 30
, 2020.
She pointed out that the molecular mechanism of combining the two drugs can be jointly explored as soon as possible when sufficient; When carrying out combination drugs, the IND application
for combination drugs should be submitted in accordance with Article 27 of the Measures for the Administration of Drug Registration.

In the selection of study endpoints, the dual clinical endpoint combination generally includes ORR/PFS, ORR/OS, PFS/OS, suitable double endpoints should be selected according to the action characteristics of different drugs of chemotherapy, antivascular and immunotherapy; The effectiveness of surrogate endpoints determines whether they can be declared in advance, and significant surrogate endpoints are likely to translate into benefits
for clinical endpoints.
She cautions that if the benefits are only surrogate, they do not necessarily lead to the ultimate benefits
for patients.

Finally, she talked about the inevitable fact that many applicants are driven by capital to quickly chase global hot targets through literature
.
"But can all of the findings in these literature be effective therapeutic targets?" What is the most suitable treatment for the patient? She questioned the attendees
.

New drug research and development seems to be blind, but she encouraged industry peers to say: "R&D is endless, we should strengthen basic research, strengthen the overall understanding of the disease, strengthen multidisciplinary cooperation based on patient-centered new drug research and development, and improve R&D efficiency
with new research methods.
" In clinical trials, researchers face real patients, in order to give researchers maximum support, CDE has developed a number of patient-centered guidelines, hoping to promote the development of new drugs and provide technical services
for the industry.
”

Charlene: Clinical development and review consideration of anti-tumor ADC

Reviewer of CDE Chemical Drug Clinical Department Chief Reviewer Charlene

Charlene, the chief reviewer of CDE Chemical Drug Clinical Department, introduced the R&D overview of global and Chinese anti-tumor ADCs, the key elements of clinical trial design, review considerations, and the "Technical Guidelines for Non-clinical Research of Antibody Conjugate Drugs (Draft for Comments)
" issued on July 6 this year.

It can be seen that domestic ADC drug development targets are still concentrated in HER2, TROP2, Claudin18.
2
.
According to the research report of Southwest Securities, there are more than 170 ADCs under research in China, of which nearly 60 have entered the clinical stage
.
Charlene introduced the CDE anti-tumor ADC review considerations: study population, dose exploration, combination therapy strategy, and risk control
.

In the study population, in addition to target receptor expression on tumor cells, a more comprehensive strategy can be used, including markers
related to the ADC mechanism of action.

In terms of dose exploration, Charlene suggested that animal doses be converted to human doses equivalent between species, that a wide dose range be used in the first human study, and that multiple different doses be selected in early trials to evaluate the safety and activity
of ADC molecules.

Currently, there are 36 trials registered in CDE that are in progress in combination ADC drugs and immuno-oncology (IO) therapy, most of which are immune checkpoint inhibitors, and these studies have shown that when ADC drugs are used in combination with immunotherapy, they can synergize anti-tumor activity and increase efficacy
.

In terms of risk control, Charlene reminded that ADCs with the same target and similar payload have limited safety risk characteristics and R&D experience that can be referenced to each other during the development process, and the monitoring
of ADC drug safety should be strengthened.

Tong Xin: Review and consideration of the best dosing strategy for clinical development of antitumor drugs

Reviewer of CDE Chemical Drug Clinical Department Tong Xin

Dr.
Tong Xin, a reviewer of the first clinical department of CDE chemical drugs, pointed out that the common dosage strategies in the current clinical trials of antitumor drugs include accelerated titration design, "3+3" dose escalation, and restricted toxicity according to dose (DLT) Determine the maximum tolerated dose (MTD), reduce 1~2 doses, and expand to determine the recommended dose (RP2D) and phase III study dose
under the condition of ensuring safety.

Inappropriate dosing strategies will result in no increase in efficacy and increased adverse effects; Therefore, the dosing strategy is a key element
of drug success.
Tong Xin introduced the focus of regulators on how to optimize drug delivery strategies, while CDE advocates optimized drug delivery strategies
in a number of guiding principles.

So, how should a dosing strategy be developed? She suggests that the optimal drug delivery strategy
needs to be individualized and combined with various data.
Whether monotherapy or in combination, the best dosing strategy is the effective dose with the highest efficacy and the effective dose
with the lowest toxicity.
Drug delivery strategies should be developed based on molecular mechanisms and non-clinical findings, using biomarkers, while focusing on adverse effects
.

She looks forward to optimizing the dosing strategy before marketing as the key to the development of anti-tumor drugs: patient-centric, fully explore early trials, formulate development plans as a whole, and strengthen communication
.

Li Jian: Development of antitumor drugs guided by the MIDD model

Jian Li, Reviewer, Department of Statistics and Clinical Pharmacology, CDE

Li Jian, an evaluator of the Department of Statistics and Clinical Pharmacology of CDE, also emphasized the importance of reasonable dosing dose, and the whole process of drug development is to explore and select the most suitable dose to do, and verify the safety and effectiveness
of a certain dose.
He introduced Model-Informed The concept of Drug Development (MIDD) and how to guide new drug development
.

MIDD played an important role
in the entire trial process.
The policies issued by CDE include the Technical Guidelines for Model-Guided Drug Development (December 31, 2020); Technical Guidelines for Population Pharmacokinetic Research (December 31, 2020); Technical Guidelines for Clinical Pharmacology Research of Innovative Drugs (December 17, 2021).

The guidelines related to MIDD in antineoplastic drugs include, "Technical Guidelines for the Extended Cohort Study of the First Human Trial of Antineoplastic Drugs (Trial)" (December 22, 2021); Guidelines for Clinical R&D of Antitumor Drugs Guided by Clinical Value (November 15, 2021); Technical Guidelines for the Application of Biomarkers in the Clinical Development of Antitumor Drugs (December 6, 2021).

He recommended that quantitative pharmacology professionals be involved in trial design as early as possible, summarized as follows: • MIDD is used to guide companies in early dose exploration and dose optimization; • The use of MIDD in new drug research and development should run through the whole process from non-clinical to clinical research, and more and more biotechnology companies are beginning to use models to guide drug development; • Increase the use of biomarkers and dose-response in the development of antineoplastic drugs; • Making a model is like a snowball, the more data accumulated, the more reliable the model, fully mining and collecting the data available in clinical trials, and comprehensively carrying out analysis is of great significance
to improve the accuracy of model decision-making.

He recommends that quantitative pharmacology professionals be involved in trial design as early as possible, which is summarized as follows:

Tang Ling: Single-arm clinical trials support the review and consideration of antitumor drug marketing

Reviewer of CDE Chemical Drug Clinical Department Tang Ling

Tang Ling, reviewer of CDE Chemical Drug Clinical Department, introduced the single-arm clinical trial
.
Because single-arm clinical trials enable drugs with more precise treatment and more outstanding efficacy to be launched faster, they have attracted much attention
from regulators and enterprises in various countries in recent years.
She joked that when applicants consult with CDE reviewers, the first question is that they plan to conduct a one-arm trial.
Tang Ling believes that of course, applicants can carry out one-arm experiments, but not blindly
.

In terms of regulatory technical requirements, CDE Document No.
40 of 2020 issued the "Technical Guidelines for Pre-clinical Communication and Exchange of Antitumor Drugs Supported by Single-arm Trials for Marketing Purposes" (December 2, 2020) and the "Technical Guidelines for Communication and Exchange of Antitumor Drugs Supported by Single-arm Trials to Enter Key Pre-trial Clinical Aspects" (December 2, 2020) issued on 47 December 2020, as well as the "Technical Guidelines for Applicability of Single-arm Clinical Trials to Support the Marketing Application of Antitumor Drugs" issued in June 2022 (June 20, 2022).

These guidelines set standards for communication and listing applications for the industry
.

The applicability of single-arm studies includes when there is no effective treatment in the study population, when the mechanism of action of the experimental drug is clear, when the past indication data of a drug is clear, when two or more doses are recommended when reasonable doses, when the test drug has outstanding effectiveness (if there is significant ORR), when safety and risk are controllable (estimated safety exposure is 300 cases), and if it is a rare tumor, it can also be applied to single-arm research
.

Tang Ling emphasized that applicants must have accurate research plans and single-arm trial designs, and whether they can finally obtain conditional approval for marketing depends on whether the indications can obtain effective and safe treatment
.
Some companies asked: If two companies do single-arm trials of the same drug at the same time, how should they respond? Tang Ling said that whether it can be listed is based on whether the medical practice is truly beneficial to patients, depending on the applicant's planning
.
She concluded that single-arm studies are only an option when RCTs are difficult to conduct, and that single-arm trials need to be treated with greater caution and the need to provide patients with drugs that benefit more than risk early
.

Zou Limin: China accelerates the implementation and challenges of listing registration procedures

Zou Limin, chief reviewer of CDE Chemical Drug Clinical Department

Zou Limin, chief reviewer of CDE Chemical Drug Clinical Department, introduced the three accelerated registration procedures in the "Measures for the Administration of Drug Registration" implemented in July 2021 - breakthrough therapy, conditional approval and priority review and approval system
.

She uses a vivid metaphor: breakthrough therapy-eligible drugs are in phase I and II studies, which is equivalent to the drug candidate being selected as "three good students; Conditional approval is equivalent to students who are guaranteed to university with excellent grades, and the R&D cycle is shortened
.
The priority review means that students with good results in independent enrollment of colleges and universities can issue admission notices
in advance.
If breakthrough therapy is to be applied, the mechanism of action and efficacy of the drug must be good enough, and the disease mechanism, epidemiological and historical research data and clinical needs must be clear
enough.

When introducing conditional approval, she pointed out: "The accelerated process of conditional approval requires several determinants, such as solid clinical data before conditional approval, and if the drug without clinical benefit is identified and terminated as soon as possible, the conditional approval process is guaranteed and the success rate
is improved.
" ”

Zou Limin introduced that conditional approval does not mean reducing the requirements for clinical research data, and there is a lack of confirmatory research results during conditional approval, and the degree of matching between the drug treatment mechanism and the disease occurrence mechanism is required; Solid dosing/regimen basis; Clinical study data must include results and analysis of clinical endpoints; Predict the impact of
drug safety characteristics on the final benefit risk assessment.

She proposed setting a reasonable time limit for confirmatory evidence, which includes thinking about the nature of approval and the nature of science
.
Among them, the approval attribute means that the conditional approval registration certificate is usually valid for no more than 5 years; Scientific attributes mean that applicants need to respect the scientific rules
of drug development for different indications.

Under the new situation, CDE has new thinking
on priority review and approval.
For example, the Opinions on Deepening the Reform of Drug Review and Approval to Further Encourage Drug Innovation issued in 2013 proposed to accelerate the review of innovative drugs; In 2015~2016, the "Opinions on Reforming the Review and Approval System for Drugs and Medical Devices" issued by the State Council optimized the review and approval procedures for innovative drugs and accelerated the review of innovative drugs urgently needed in clinical practice; The Opinions on Deepening the Reform of the Review and Approval System to Encourage Innovation in Drugs and Medical Devices issued in 2017; The 2020 Measures for the Administration of Drug Registration focus on rare diseases, pediatric drugs, innovative drugs with outstanding efficacy that are urgently needed in clinical need and improved new drugs
.

"At each stage, NMPA has clear review and approval endpoints, time limits and policy support
.
" Zou Limin said
.

Experts from Chinese clinical oncologists attending the meeting said , new drug research and development can not only focus on the specific batch of a certain variety or not approved, but should be guided by clinical value
.
Through the sincere cooperation between CSCO and CDE for six years, both parties have a deeper understanding and understanding of anti-tumor drugs from clinical project approval to trial design, and finally work together to bring new drugs to market and benefit patients, which is the common goal
of clinical, review and institutions.

CSCO Annual Meeting Site Atlas

Some CSCO experts took a group photo
with the CDE tumor review team.
This CDE oncology review team is very professional, full of vitality and vitality
.

In his closing speech, Professor Li Jin emphasized that applicants should not only focus on whether the current variety is approved, but always keep patients in mind to develop real good drugs
.

Professor Xu Ruihua of Sun Yat-sen University Cancer Center commented
on the spot.

Professor Shen Lin of Peking University Cancer Hospital called on more developers to pay attention to the research and development
of new drugs for digestive tract cancer, which is highly common in China.

Professor Guo Jun from Peking University Cancer Hospital asked questions
on the spot.

Professor Wang Jie (first row right of screen), Professor Wu Yilong of Guangdong Provincial People's Hospital (second row of screen, right), Professor Li Jin (second row left of screen), Professor Wu Lingying (second right of stage), Yang Zhimin (first right of stage) and Zou Limin (first left of stage) interact.

Yang Zhimin (right) interacts
with Professor Wu Lingying from the Cancer Hospital of the Chinese Academy of Medical Sciences.

Professor Shen Lin (right) interacts with Professor Jiang Zefei from the PLA General Hospital
.

Professor Ma Jun of Harbin Institute of Hematology and Oncology delivered a speech
.

Professor Qin Shukui of Qinhuai Medical District, General Hospital of the Eastern Theater, delivered a speech
.

About CSCO's mission and history

The Chinese Society of Clinical Oncology (CSCO) was established
in Beijing in 1997.
CSCO is committed to continuing education in clinical oncology and carrying out multi-center and multidisciplinary collaborative research in accordance with GCP, actively promoting the standardization of tumor diagnosis and treatment, improving the academic level of clinical oncology in China, and carrying out international and domestic academic exchanges and scientific and technological cooperation
with relevant academic groups at home and abroad.
Calendar number CSCO The milestones of the past 25 years mainly have six aspects, which fully reflect CSCO's purpose of "unity, cooperation and pragmatism" and the principles of "public welfare, scholarship and dedication", and help "Healthy China" make important contributions
.

Build a continuing education platform and establish a CSCO organization

In April 1997, the first CSCO Annual Conference was held

Source| CSCO 20th Anniversary Booklet

1997 Over the past year, more than 200 Chinese oncologists have paid special attention to the rapid development of clinical oncology and the rise of international multi-center clinical research, but because there is no similar platform or organization in China, after multi-party consultation and the approval of the Ministry of Health and the Ministry of Science and Technology, they officially established the "Clinical Collaboration Center of the Chinese Anti-Cancer Association" (externally known as CSCO) in Beijing Hotel on April 30, mainly positioned to carry out extensive clinical oncology continuing education.
Actively promote multidisciplinary collaboration among Chinese oncologists and carry out international and domestic multi-center clinical trials
.
CSCO The establishment of the medical community marks the unity of the national clinical oncology community and is a milestone event
of great significance in the medical community.

Strengthen exchanges and cooperation and integrate with international academia

Since 2014, CSCO has successively opened international special sessions, jointly held with ASCO, ESMO and other internationally renowned societies

Source| CSCO <>th Anniversary Booklet

CSCO At the beginning of its establishment, it established close ties with the American Society of Clinical Oncology (ASCO) and the International Union Against Cancer (UlCC), and later reached mutual recognition and reciprocity, in-depth exchanges and scientific and technological cooperation with clinical oncology societies in Europe, Russia, Japan, South Korea and other countries and regions, which played an important role
for Chinese scholars to learn advanced and integrate into the world anti-cancer stage.
Today, CSCO It has become a world-renowned international academic organization
.

Patrol the remote and grassroots to benefit the majority of patients

China has a vast territory, uneven economic and health development, and uneven distribution of medical resources, CSCO actively responds to the call of the state, carries out public welfare activities such as "western trip", "grassroots trip", insists on extending clinical oncology continuing education to western provinces and cities, remote areas and grassroots hospitals, and strives to improve the professional level of doctors, so that patients in these places can enjoy homogeneous treatment
with developed central and coastal areas.

Documenting progress is more about looking to the future

In 2015, CSCO officially became a national level society

Source| CSCO <>th Anniversary Booklet

CSCO pays great attention to summarizing experience and lessons
.
From 2015 Since then, CSCO has begun to compile the "Annual Research Progress of Clinical Oncology in China", collecting clinical and scientific research data, compiling clinical research results with significant impact led by Chinese scholars, recording the chronicle of clinical oncology in China, and encouraging members to learn and innovate
.

Formulate a series of guidelines for the diagnosis and treatment of cancer in China

It is an important task
of CSCO to promote the professionalization and standardization of diagnosis, treatment and research in China with patients as the center.
To this end, 2012 post-CSCO Launch of a series of expert consensus and practical guides
.
In addition to reflecting the most cutting-edge academic views and progress, it emphasizes taking into account factors such as China's national conditions, individual differences of patients and drug accessibility, and strives to be "faster, newer and more detailed", which is scientific, advanced and operational
.
The launch of CSCO consensus and guidelines has had a huge and far-reaching impact on changing the landscape and outcomes of clinical oncology treatment in China, 4 per year The CSCO will hold a general meeting every month to revise the guidelines
.

Set up a CDE special session to build a communication platform

According to Professor Qin Shukui, Vice Chairman of CSCO, Eastern Theater General Hospital, and Liu Ling, Director of the CSCO Office, CSCO-CDE The predecessor of the special session was the "Anti-Cancer Drug Research and Evaluation Forum"
at the 2010 CSCO Annual Conference.
At that time, CSCO realized that the R&D and review of new anti-tumor drugs needed to be integrated with international authoritative review institutions (such as the US FDA and European EMA), so it invited the reviewers of the US FDA and the reviewers of China CDE to give a speech on the same stage, so that the domestic medical community could fully understand the concept
of new drug development and review in China and the United States.

Since 2016, under the strong encouragement of the grand strategic decision of "Healthy China", domestic local biopharmaceutical companies have sprung up, and most of them are engaged in the research and development of new anti-tumor drugs, in order to actively promote the local innovative oncology drug research and development and clinical trials, with the support of the State Food and Drug Administration, the previous "Anti-cancer Drug Research and Evaluation Forum" has been transformed "CSCO-CDE Session"
.

The special session is usually co-hosted by CSCO and CDE leaders, and the reviewers of the CDE oncology drug review team are specially invited to give special academic reports, focusing on the international and domestic situation, dynamics and data of anti-tumor new drug research and development, selecting and interpreting CDE's technical guidelines for the clinical development of anti-tumor drugs and CDE review of risks and benefits and other hot spots, and conducting face-to-face discussions and exchanges with the representatives participating in the conference with specific cases, with lively form and rich
。

According to Yang Zhimin, deputy director of CDE, "Every year, CDE will use this special session to fairly, openly and scientifically publicize the new policies and principles of NMPA; Solve some difficulties encountered by everyone in the clinical trial process, and send the signal of regulatory agencies to support the development of the pharmaceutical industry and support innovation, so as to better serve
patients.
"Since its establishment, this special session has received the attention
of national anti-tumor drug developers and clinicians every year.
This year was held during the intense period of epidemic prevention and control, and the number of online participants was as high as 500,000!

For 25 years, CSCO's "old, middle-aged and young" sincerely unites, serves the national clinical oncology workers, carries out relevant academic activities in an all-round way, organizes medical continuing education, compiles and publishes academic journals and formulates clinical guidelines, and comprehensively popularizes scientific knowledge
of cancer prevention and treatment 。 CSCO has gone through a splendid development road from scratch, from weak to strong, and now allows Chinese oncologists and scholars to bloom on the world stage, introduce research results and experience from China, and has become one of the most active, well-known and important authoritative professional academic groups in the global clinical oncology community, comprehensively promoting the vigorous development of international and domestic anti-tumor causes, and has produced a huge and far-reaching impact
.

This article is especially thanks to the Chinese Society of Clinical Oncology (CSCO) Vice Chairman and Chief Physician of Qinhuai Medical District of Eastern Theater General Hospital, Professor Qin Shukui, Director of CSCO Office Liu Ling, and Doctor Jiang Jianhua, Editor-in-Chief of Medicine Cube!

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