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.

Accestra Consulting Provides China Regulatory Affairs Outsourcing for:

• Drugs/Pharmaceutical,
• Food and Feed products for China NMPA (Formerly CFDA),
• Regulatory approval including product registration for China Investigational New Drug (IND),
• China New Drug Application (NDA),
• China Drug Master File (DMF) for APIs,
• Excipient and Packaging Materials,
• ANDA,
• eCTD submission and others.

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In 2019, CDE administratively approved a total of 5983 registration applications for chemical drugs, traditional Chinese medicines and biological products (excl. registrations for provincial review), among which technical review was required for 4075 registration applications and the others (supplementary applications and approvals for temporarily imported drugs) could be approved directly.

Among 4075 registration applications reviewed and approved by CDE, the number of approvals for each application type is listed in Table 1 below.

Table 1. Number of Administrative Approvals for each application type in 2019.

According to the regulatory requirements for IND registration, IND approvals were issued by default within 60 days upon positive results of technical review by CDE. Including the approvals issued during the technical review of ANDAs for supplementary clinical trials, CDE issued a total of 1178 notifications of clinical trials in 2019. They were 1066 clinical trial (IND) approvals and 112 suspension notifications of clinical trials.

Among the approved registration applications, 1908 applications were approved directly by NMPA or CDE without being technically reviewed, including 1491 supplementary applications and 417 approvals for temporarily imported drugs.

The average timeline of administrative approval was 9.9 workdays, whereas the stipulated timeline was 20 workdays of each approval.

1905 Applications were approved within the stipulated timeline, which gave 99.8% of on-time completion of the year.

In order to reduce the backlog of registration applications and promote drug innovations, China Center for Drug Evaluation (CDE) accepted 253 applications for priority review of drug registrations in 2019, representing a decline of 19.2% from the last year.

The table below (Table 2) shows the number of applications accepted for priority review under each registration classification/application type from 2016 to 2019.

The most applications accepted for priority review in 2019 were registrations for new drugs with substantial clinical benefit (34%) followed by parallel registration applications (28.1%).

Comparing to the previous year, the number of registration applications for new drugs with substantial clinical benefit increased from 23% to 34%, whereas the number of re-applications for generics after consistency evaluation decreased from 16.6% to 7.9%.

As indicated by the data, the number of generic registrations has declined continuously so that more and more registrations of innovative new drugs with substantial clinical benefit or urgent medical needs could be reviewed with priority.

There were 143 registration applications (82 drug categories) approved for priority review and issued with marketing authorizations with acceleration, such as chemical drug Class 1 Innovative New Drug, i.v. Remimazolam Tosylate and Sodium Oligomannate Capsules. The table below (Table 3) shows the number of drug categories of accelerated approvals from 2016 to 2019.

The drug category of a chemical drug is referred to as the active pharmaceutical ingredient for the making of that drug, whereas the drug category of a biological product or traditional Chinese medicine is referred to as the international nonproprietary name (INN) of that drug.

Table 2. Number of Applications Accepted for Priority Review from 2016 to 2019.

In order to guide applicants through drug registration and further improve the support for drug innovations, CDE increased the number of communication channels and improved communication effectiveness in 2019.

These communication channels include meetings, Q&As for general technical issues, consultations by telephone, E-mails and on-site communication.

In the new model of multi-channel communication, 2633 applications were received for CDE meetings with an increase of 32.8%, among which 1871 applications were approved with an increase of 41.1%.

On the internet platform of CDE, 16572 questions were received for general technical issues with an increase of 8.9%.

The figures below (Fig. 1 and 2) show the number of applications respectively for CDE meetings and general technical issue Q&As from 2016 to 2019.

Among 1871 approved applications for CDE meetings, Class II meetings shared 71.8% of total approvals. The most requested Class II meeting was pre-IND meeting with a ratio of 34.9% of all approved meetings. An overview of all approved CDE meetings is given in the table below (Table 4).

Table 4. Overview of CDE Meeting Applications approved in 2019.

When holding meetings, CDE arranged either face-to-face (F2F) meetings or e-conferences through video or phone call. In 2019, 421 meetings were held with an increase of 30.7%. The table below (Table 5) shows the number of CDE meetings being held under each classification from 2018 to 2019.

Table 5. Number of CDE Meetings being held from 2018 to 2019.

Among 16572 questions received for general technical issues on the platform of CDE, most questions were for:

• Active Pharmaceutical Ingredients (APIs),
• Excipients and packaging materials (4152 questions),
• Followed by application acceptance of drug registration (1846 questions).

Chemical drugs remained the most concerning products for drug registration (9743 questions) with a majority of questions of generic consistency evaluation (1386 questions) and application acceptance (1174 questions).

For an overview of general technical issue Q&As in 2019, please find more details in the table below (Table 6).

Table 6. Number of Q&A’s for General Technical Issues in 2019.

In order to comprehensively review drug registration applications, the National Medical Products Administration (NMPA) of China conducted on-site inspections/audits not only for general issues but also specific problems which were reported to NMPA (“For-cause” Inspection).

The table below (Table 7) shows the number of tasks and reports achieved respectively for general and “for-cause” inspections/audits in 2019.

Table 7. Overview of on-site inspection & audit in 2019.

Accestra Consulting Provides China Regulatory Affairs Outsourcing for:

• Drugs/Pharmaceutical,
• Food and Feed products for China NMPA (Formerly CFDA),
• Regulatory approval including product registration for China Investigational New Drug (IND),
• China New Drug Application (NDA),
• China Drug Master File (DMF) for APIs,
• Excipient and Packaging Materials,
• ANDA,
• eCTD submission and more.

For queries, please contact us: info@accestra.com

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China DMF Filing Process

Does China DMF comply with US FDA or EU EMA Requirements?

China DMF Summary

DMF Policy Update (August 2019)

On July 16, 2019, China NMPA published the new DMF requirements (Announcement No. 56 of NMPA, 2019), which was a major update to DMF filing for APIs, pharmaceutical excipients & packaging materials.

Key takeaways of the new requirements are below:

• Risk-based evaluation for excipients and packaging materials.
• Annual report being submitted every first quarter of the year.
• List of excipients no longer required.
• Previously approved APIs in China are exempted from drug-related associated review.
• Dossier requirements and workflow simplified.
• Find out more about the DMF policy update.

Is China DMF ECTD Ready?

Announcement No. 146, 2017 (published by the former China Food and Drug Administration (CFDA))

Announcement No. 56, 2019 (issued by China National Medical Products Administration (NMPA))

Table 1. Number of applications reviewed and approved in 2019.

For applications under or pending for review and approval, the number of applications under each status is listed in Table 2. For applications with completed technical review, the number of applications under each drug classification is listed in Table 3.

Table 2. Number of applications under or pending review and approval in 2019.

Table 3. Number of applications with completed technical review of 2019.

In 2019, CDE completed the technical review for 6817 drug registration applications, among which the number of applications of each application type is shown in the diagram below (Fig. 1) along with the data from 2016 to 2018.

The table below (Table 4) shows the number of applications approved under each registration classification of chemical drugs, including Investigational New Drug (IND), New Drug Application (NDA) and Abbreviated New Drug Application (ANDA). As highlights, 493 applications for Class 1 Innovative New Drug were approved under IND registration while 260 applications for oral solid dosage forms were approved under ANDA.

Table 4. Number of applications approved under each chemical drug registration classification.

In 2019, CDE completed the technical review for 5413 chemical drug registration applications, among which the number of applications of each application type is shown in the diagram below (Fig. 2).

Among the chemical drug registration applications, 3412 applications were approved for technical review. For each application type, the number of approvals is listed in Table 5.

Under the registration classification New Drug Application (NDA), 88 applications were approved in 2019.

For a comparison with the last three years, the numbers of approvals from 2016 to 2019 are shown in the diagram below (Fig. 3).

Table 5. Overview of approvals for Chemical Drug Registrations in 2019.

Among the 189 drug categories, anti-neoplastic, gastrointestinal, anti-infective and nervous system drugs covered 70% of the approvals. The diagram below (Fig. 5) shows the number of drug categories for each indication where Class 1 IND applications were approved in 2019.

In 2019, CDE completed the technical review for 300 traditional Chinese medicine registration applications, among which the number of applications of each application type is shown in the diagram below (Fig. 6).

Among these registration applications, 15 IND applications and 2 NDAs for traditional Chinese medicines were approved for technical review.

For each application type, the number of approvals is listed in Table 6.

For a comparison with the last three years, the numbers of IND/NDA approvals from 2016 to 2019 are shown in the diagram below (Fig. 7).

Table 6. Overview of approval for Traditional Chinese Medicine registrations in 2019.

The approved traditional Chinese medicine IND registrations covered 10 indications, among which 10 approvals were for:

• cardiovascular,
• gastrointestinal,
• anti-neoplastic,
• respiratory,
• urological drugs (67% of the total number).

The diagram below (Fig. 8) shows the number of approvals for each indication of traditional Chinese medicine IND registrations in 2019.

In 2019, CDE completed the technical review for 1104 biological product registration applications, among which the number of applications of each application type is shown in the diagram below (Fig. 9).

Among these registration applications, 312 IND applications and 74 NDAs for biological products were approved for technical review. For each application type, the number of approvals is listed in Table 7. For a comparison with the last three years, the numbers of IND/NDA approvals from 2016 to 2019 are shown in the diagram below (Fig. 10).

Table 7. Overview of approvals for Biological Product REgistrations in 2019.

For biological INDs, anti-neoplastic treatment was a hot topic in drug development and covered 50% of the approvals. Meanwhile, half of the biological NDA approvals were for anti-neoplastic and endocrine treatment.

The diagrams below (Fig. 11 and 12) show the number of approvals for each indication of biological IND and NDA registrations respectively in 2019.

Accestra Consulting Provides China Regulatory Affairs Outsourcing for:

• Drugs/Pharmaceutical,
• Food and Feed products for China NMPA (Formerly CFDA),
• Regulatory approval including product registration for China Investigational New Drug (IND),
• China New Drug Application (NDA),
• China Drug Master File (DMF) for APIs,
• Excipient and Packaging Materials,
• ANDA, eCTD submission and others.

For queries, please contact us at: info@accestra.com

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1. Overall Summary

The diagram below (Fig. 1) compares registration amounts among different drug products from 2016 to 2019. 80.2% of drug registrations approved in 2019 were for chemical drugs, which had 6475 registrations.

The diagram below (Fig. 2) shows the number of drug registrations approved through technical review from 2016 to 2019. In 2019, a total of 6199 drug registrations were approved through technical review, an increase of 11.21% over last year.

Table 2. Number of Drug Registrations Approved through Tenchical Review in 2019.

Table 3. Number of Drug Categories of Innovative New Drugs Approved in 2019.

2. Domestic Innovative New Drugs

Table 4. Number of Registrations and Categories of Domestic Innovative New Drugs Approved in 2019.

3. Imported Innovative New Drugs & Original Drugs

The table below (Table 5) shows the number of drug registrations as well as categories of imported innovative new drugs and original drugs respectively. The indications of these drugs are mainly cancers, endocrine and neurological disorders.

Table 5. Number of Registrations and Categories of Imported Innovative New Drugs & Original Drugs Approved in 2019.

4. Analysis of Drug Registrations

4.1 Analysis of Chemical Drug Registrations

4.1.1 Analysis of IND and NDA Registrations

In 2019, CDE approved 444 IND registrations for domestic chemical drugs and 250 IND registrations for imported chemical drugs.

The indications of domestic INDs are mainly cancers, gastrointestinal disorders, and infectious diseases, whereas the indications of imported INDs are mainly cancers, infectious diseases, and neurological disorders.

The diagram below (Fig. 5) shows the number of approved IND registrations for different indications of both domestic and imported chemical drugs in 2019.

In 2019, CDE approved 45 NDA registrations for domestic chemical drugs and 85 NDA registrations for imported chemical drugs.

The indications of domestic NDAs are mainly cancers and infectious diseases, whereas the indications of imported NDAs are mainly cancers and neurological disorders.

The diagram below (Fig. 6) shows the number of approved NDA registrations for different indications of both domestic and imported chemical drugs in 2019.

4.1.2 Analysis of Innovative New (Chemical) Drug Registrations

In 2019, CDE approved 573 innovative new drug registrations for chemical drugs under registration Class 1, which covered 219 drug categories.

The table below (Table 6) shows the number of chemical drug categories of IND and NDA registrations respectively.

Table 6. Number of Drug Categories of IND/NDA Registration Approved in 2019.

The diagram below (Fig. 7) shows the number of approved innovative new drug registrations for domestic and imported chemical drugs respectively from 2016 to 2019.

4.2 Analysis of Traditional Chinese Medicine Registrations

In 2019, CDE approved 423 traditional Chinese medicine registrations, including 17 IND registrations, 3 NDA registrations and 3 ANDA registrations.

The diagram below (Fig. 8) shows the number of traditional Chinese medicine registrations approved for all application types in 2019.

For new or generic traditional Chinese medicines, the number of registrations approved from 2016 to 2019 is shown in another diagram below (Fig. 9) respectively for INDs, NDAs, and ANDAs.

For innovative new traditional Chinese medicines, 17 IND registrations were approved by CDE in 2019, which were mainly indicated for the treatment of gastrointestinal, respiratory and orthopedic disorders.

4.3 Analysis of Biological Product Registrations

In 2019, CDE approved 1179 biological product registrations, including 310 IND registrations and 124 NDA registrations.

IND registrations had an increase of 4% over the last year, and NDA registrations had an increase of 45.9%.

The diagram below (Fig. 10) shows the number of biological product registrations approved for all application types in 2019. For new or generic biological products, the number of registrations approved from 2016 to 2019 is shown in another diagram below (Fig. 11) respectively for INDs and NDAs (preventative or therapeutic).

4.3.1 Analysis of Innovative New Biological Product Registrations

In 2019, CDE approved 127 innovative new drug registrations for biological products under registration Class 1, including 2 preventative and 125 therapeutic biological products.

The table below (Table 7) shows the number of drug registrations as well as categories of innovative new biological products respectively for INDs and NDAs.

Table 7. Number of Registration and Categories of Innovative New Biological Products Approved in 2019.

119 therapeutic biological products were approved for IND registrations under registration Class 1.

These products covered 95 drug categories and were mainly indicated for the treatment of cancers.

The diagram below (Fig. 12) shows the number of approved IND registrations for different indications of therapeutic biological products in 2019.

Accestra Consulting provides services for:

• China Regulatory Affairs Outsourcing for Drugs/Pharmaceutical,
• Food and Feed products for China NMPA (Formerly CFDA),
• Regulatory approval including product registration for China Investigational New Drug (IND),
• China New Drug Application (NDA),
• China Drug Master File (DMF) for APIs,
• Excipient and Packaging Materials,
• ANDA,
• eCTD submission and more.

For queries, please contact us at: info@accestra.com