China Drug Evaluation Report 2019 by CDE – –– Part 4. Priority Review, CDE Meetings, NMPA Inspection & Approval

In 2019, the Center for Drug Evaluation (CDE) of China reviewed and approved a total of 8730 drug registration applications.

As a follow-up on part 3 of Drug Evaluation Report 2019, part 4 further gives an overview of new drug approvals for hot topics in drug therapy and major regulatory events/reforms of 2019 summarized by CDE, incl. drug approvals for urgent clinical needs, generic consistency evaluation, regulatory reforms, and improvements on drug registration.

Under a total of 28 drug categories, new drugs were approved in 2019 for hot topics in drug therapy, e.g., anti-neoplastic drugs, anti-infective drugs etc. The indications and categories of these drugs are given in the table below (Table 1).

Table 1. Overview of 2019 New Drug Approvals for Hot Topics in Drug Therapy.

Accelerating the approval for new drugs which have been marketed overseas and were of urgent clinical need in China was one of the key tasks for the Center for Drug Evaluation (CDE) in 2019.

CDE has selected a total of 74 drugs under this category and made a proactive approach of providing regulatory support for the overseas marketing authorization holders (MAH), incl. guidance on new drug registration, the workflow of priority review & accelerated approval, dossier requirements, and acceptance of foreign clinical data.

Under these actions, 16 imported new drugs of urgent clinical need were approved in 2019 with an increase of 60%. These applications were reviewed and approved within the timeline stipulated by NMPA, among which imported drugs for rare diseases were approved within three months and other imported drugs of urgent clinical need were approved within six months.

The accelerated approval reduced the time interval between drug marketing outside and inside of China.

The registration status of the imported new drugs of urgent clinical need in 2019 is shown in the table below (Table 2).

Table 2. Drug Registration Status 2019 of Imported New Drugs of Urgent Clinical Need.

In 2019, China CDE issued a series of technical guidelines and regulatory support to further implement the consistency evaluation of generics applying for China drug registration.

1. Reference Listed Drug (RLD) Selection: in order to standardize the workflow of RLD selection and determination, CDE legislated and NMPA issued the Procedures of RLD Selection and Determination for Chemical Generics (NMPA [2019] Decree No.25). Under the framework of RLD selection, 1899 RLDs of 22 lists have been released by NMPA, including 748 RLDs of 3 lists released in 2019.
2. Specific Generics of China Exclusive Marketing Authorization: for some specific generics of China exclusive marketing authorizations, CDE issued the Advice on Evaluating Specific Generics of China Exclusive Marketing Authorization on 21. June 2019 to guide the consistency evaluation of these drugs.
3. Information Publicity and Communications: in 2019, CDE established a platform on its official website especially for publishing information on generic consistency evaluation. Drug labels/package inserts, company investigation reports, data of bioequivalence study and information on technical training programs could be found on this platform. Other communication channels, such as public consulting days, gateway for applicant, phone and written consulting enabled CDE to provide regulatory guidance and support to application for generic consistency evaluation.
4. Technical Requirements: in order to further define the general plan and technical requirements for generic consistency evaluation of injectable chemical drugs, CDE legislated the Technical Requirements for Consistency Evaluation of Marketed Injectable Chemical Generics, Application Dossier Requirements for Consistency Evaluation of Marketed Injectable Chemical Generics and Technical Requirements for Consistency Evaluation of Injectable Chemical Generics with Special Features in 2019.
5. Bioequivalence Study: for bioequivalence study on chemical drugs, 442 applications for generic registration and 737 applications for generic consistency evaluation were submitted to CDE’s platforms in 2019.

According to the Drug Administration Law (State Council of the People’s Republic of China [2019] Decree No.31) revised and issued in 2019, a pharmacovigilance system shall be established to monitor, identify, evaluate and control adverse drug reactions and other harmful reactions to medicines. For safety issues or other risks identified during clinical trials, the registrant of clinical trials shall modify, suspend or terminate clinical trials and report the cases to National Medical Products Administration (NMPA).

In 2019, CDE issued approvals for clinical trials (IND approvals by default) on 432 drugs of 164 Research and Development (R&D) companies worldwide. The overview of this year’s pharmacovigilance case reporting is given in the table below (Table 3).

Table 3. Overview of 2019 Pharmacovigilance Case Reporting

1. Improved System of Compliance Review and Inspection: CDE has established a bidirectional and parallel risk management system of reviewing drug registrations based on drug safety, meanwhile conducting compliance inspection on applicants of the related drugs.
2. Compliance Database: CDE has established a compliance database for R&D and manufacturing, which further supported the simultaneous proceeding of technical review and compliance inspection.
3. Simultaneous Proceeding of Compliance Review and Inspection: CDE has further promoted technical review, compliance inspection and sample testing being conducted simultaneously for drug registrations while remaining good coordination between its departments, such as keeping regular e-communications between CDE reviewers.

According to the requirements of the Announcement of Concerning the Further Improvement of Drug-related Associated Review & Approval and Supervision (NMPA [2019] Decree No.56), CDE improved the Active Pharmaceutical Ingredient (API) Filing Acceptance System and Technical Review System, updated the application form for API filing and relevant documents for administrative approval, established a pathway on the API filing platform for generic APIs of which the original (reference) APIs were used in finished dosage forms already being marketed in China so that these generic APIs can be reviewed and approved separately (no binding review to drugs).

In 2019, a total of 15538 APIs, pharmaceutical excipients and packaging materials were published on CDE’s platform for product filing with activated filing numbers under status “A (as Activated)”. The overview of all the published products on the platform is given in the table below (Table 4).

Table 4. Overview of Platform for API, Excipient and Packaging Material Filing.

After starting to compile the Publication of Approved Drug Products in China, CDE has recorded a total of 1055 drugs products, i.e., drugs of different international nonproprietary names (INN) and strengths.

In 2019, 430 drug products were newly included with an increase of 1.42%. The overview of the Publication of Approved Drug Products in China is given in the table below (Table 5).

Table 5. Overview of the Publication of Approved Drug Products in China.

In order to optimize the working procedures of drug registration review & approval as well as improve work efficiency, CDE refined the workflow by differentiating and simplifying each step of the technical review and administrative approval.

After nationwide investigations and surveys on local agencies and administrative authorities of drug registration, CDE further announced a variety of reforms and launched pilot projects accordingly.

The changes and measures taken in 2019 have caused an initial positive effect on the administration of drug registration review & approval in general.

In 2019, CDE participated in the legislation and revision of Drug Administration Law (State Council of the People’s Republic of China [2019] Decree No.31), Vaccine Administration Law (State Council of the People’s Republic of China [2019] Decree No.30), Provisions for Drug Registration (NMPA [2019] Draft Revision for Public Opinions) and the other 35 relevant regulations.

In order to promote the international regulatory harmonization of drug registration review & approval，CDE participated in the harmonization and implementation of International Council for Harmonization (ICH) guidelines in 2019.

1. Harmonization of ICH Topics: CDE sent regulatory experts to a total of 20 global meetings organized or held by ICH and its steering committee in 2019. Domestically, CDE organized or held a total of 263 meetings with ICH experts and settled 327 matters relevant to the harmonization of ICH guidelines.
2. Implementation of ICH Guidelines: in 2019, CDE supported NMPA in announcing the release of 43 applicable and recommended ICH guidelines, and helped organize the translation of these guidelines.
3. Organization of ICH Trainings: CDE organized 16 training courses in 2019 for a total of 2,600 staff members of drug administrative authorities in studying the ICH guidelines.

A total of 33 technical guidelines were issued by NMPA in 2019, among which 7 were formulated by CDE, such as the Technical Guidelines for Clinical Trial Endpoints of Treatment for Advanced Non-small Cell Lung Cancer.

A total of 33 technical guidelines were issued by NMPA in 2019, among which 7 were formulated by CDE, such as the Technical Guidelines for Clinical Trial Endpoints of Treatment for Advanced Non-small Cell Lung Cancer.

1. Technical Guidelines for eCTD Submission: CDE formulated technical standards and submission guidelines in 2019 for implementing electronic Common Technical Document (eCTD) in China.
2. eCTD System Testing: CDE tested the China eCTD submission system together with 10 overseas and domestic pharmaceutical companies in 2019, and further improved the system performance and workflow of submission.
3. Supporting System of eCTD Submission: the supporting system of eCTD submission in China was also improved and integrated by CDE in 2019, after which the entire process of drug registration from application submission to approval has been administrated under electronic management.
4. Communication Channel of eCTD Submission: in order to support the communication between the applicants and reviewers of drug registration, CDE established a communication channel for eCTD submission on its official website.

In order to improve the professional competence of drug registration reviewers in pharmaceutical sciences, regulatory theories and practical application, CDE formulated and implemented new regulations in 2019 for the management of reviewers training, incl. making the Management Rules of Staff Training.

Furthermore, the communication among CDE and other health authorities around the world, such as the World Health Organization (WHO), the U.S. Food and Drug Administration (U.S. FDA) and the Danish Medicines Agency, was improved in 2019. In addition, academic cooperation, communication, trainings with universities and research institutes were also improved or increased in the same year.

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• China Drug Master File (DMF) for APIs,
• Excipient and Packaging Materials,
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