The following is an overview from Accestra Consulting* of Part 1 of China’s Center for Drug Evaluation (CDE)’s 2020 reporting, including data on drug approvals for all application types (including Investigational New Drugs (INDs), New Drug Applications (NDAs), and ANDAs), hot topics within new drug approvals for 2020, and reasons for rejected applications.

 

Abstract

In 2020, the Center for Drug Evaluation (CDE) of China reviewed and/or approved a total of 11,582 drug registrations. To summarize the accomplishments and failures of drug approvals, CDE released a China Drug Evaluation Report of the year. Part 1 of the report gives an overview of drug approvals for all application types (incl. INDs, NDAs and ANDAs), new drug approvals for hot topics in 2020, and reasons for rejected applications.

 

1. Overall Summary

Under the impact of COVID-19 in 2020, the Center for Drug Evaluation (CDE) accelerated the process of drug review and approval during this public health emergency. Many more drugs (incl. drug-device combinations) were reviewed and/or approved in 2020 than the previous year, i.e., a total of 11,582 registrations with an increase of 32.67%, among which 8,606 registrations required technical review and approval whereas the others required only administrative approval. In addition, 4,882 registrations were pending for technical review. For an overview of the registrations reviewed and/or approved (incl. rejections after technical review) in 2020, please see the table below (Table 1).

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Among 8,606 registrations technically reviewed by CDE, there are 6,778 chemical drugs, 418 traditional Chinese medicines, and 1,410 biological products. Comparing with last year, the number of reviewed registrations has increased of 25.22%, 39.33% and 27.72% respectively. For a comparison between the categories and the total number of registrations reviewed from 2016 to 2020, please see the diagram below (Fig. 1).

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Fig. 1 Comparison of Drug Registrations Reviewed from 2016 to 2020. (Note: There was no registration which required only administrative approval in 2016, i.e., all registrations required technial review & approval. From 2017, specific registrations could be approved without technical review under the new regulatory framework.)

 

2. Technical Review & Approval

Among 8,606 registrations technically reviewed by CDE, there are 1,561 Investigational New Drug (IND) applications, 289 New Drug Applications (NDA), and 1,700 Abbreviated New Drug Applications (ANDA). Comparing with last year, the number of these applications has increased of 55.94%, 7.04% and 2.16% respectively. For a comparison between the categories and the total number of applications reviewed from 2016 to 2020, please see the diagram below (Fig. 2).

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Fig. 2 Number of Applications Reviewed from 2016 to 2020. (Note: CDE has started to conduct quality and efficacy consistency evaluation of generic drugs since August 2017.)

Among these applications, 1,435 INDs, 208 NDAs and 918 ANDAs were approved after technical review. These approved NDAs covered a total of 92 drug categories, including 20 categories of domestic new drugs and 72 categories of imported new drugs. The drug category of a chemical drug is referred to as the Active Pharmaceutical Ingredient (API) of the drug, whereas the drug category of a biological product or a traditional Chinese medicine is referred to as the International Nonproprietary Name (INN) of the drug.

To have an overview of the new drugs approved for hot topics in 2020, such as COVID-19 vaccines and anti-neoplastic drugs, 29 categories of NDAs are chosen and given in the table below (Table 2).

Table 2. Overview of New Drug Approvals for Hot Topics in 2020

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3. Reasons for Application Rejections

A total of 367 applications failed to get approved in 2020 because of insufficient proof for drug safety, efficacy, and quality control or delay in submitting the supplementary materials upon CDE’s requests. To have a further analysis of these application rejections, below reasons are identified from different perspectives of drug development and regulatory submission for INDs, NDAs, ANDAs, supplementary applications and others.

3.1 New Drug Application Rejections

IND Application Rejections

  • Lack of pre-IND meeting: Major data gaps were identified after filing IND applications and impossible to be supplemented in the given timeline.
  • Insufficient data for clinical development justification
    • The IND-enabling (incl. pharmaceutical, nonclinical, preclinical) studies demonstrated that the drug efficacy was low and safety risk was high. The risk–benefit ratio was not suitable for first-in-human testing.
    • The clinical development purpose did not comply with the principles of clinical trials.
    • The IND-enabling studies were not sufficient to initiate clinical trials.
  • Insufficient data to enable clinical studies or control safety risks in humans
    • Major defects in the clinical trial protocol and insufficient risk control measures.
    • Insufficient nonclinical data for combination therapy drugs.
    • Insufficient data for each individual vaccine or different immunization procedures between the individual vaccines of a combination vaccine.

NDA Rejections

  • Major defects in the research quality control and management system and therefore the submitted data could not demonstrate the safety, efficacy, and quality of the drug.
  • Regulatory incompliance
    • Inconsistent study drugs were used for different phases of clinical trials.
    • Authenticity issues were identified about clinical data during on-site inspection/audit.

ANDA Rejections

  • Unsuitable justification for generic development: the reference listed drug (RLD) which the generic compared to has been withdrawn from the market and a new drug with improved safety has been authorized for marketing in China.
  • Insufficient data for quality consistency
    • Product specification review and sample inspection did not comply with the requirements or major defects were identified in the analytical methods.
    • The bioequivalence study demonstrated that the generic and RLD were not bioequivalent.
    • Incompliance with the technical requirements for generics, such as stability testing and choose of API starting materials.
    • The APIs were not from legal sources.

Supplementary Application Rejections

  • Insufficient data to justify the change to an approved drug
    • The submitted change had major impact on the drug substance and caused substance change.
    • The submitted change to the drug label/insert did not comply with the technical requirements for drafting the drug label/insert.
  • The submitted data could not demonstrate that the change to an approved drug had no impact on the drug safety, efficacy, and quality, such as insufficient reference literature and clinical data.

Other Application Rejection

  • Biosimilars
    • Lack of similarity assessment or the choose of reference drug in the comparative study did not comply with the requirements.
    • Insufficient nonclinical/preclinical data to enable clinical studies
  • Natural Medicines: The submitted data did not comply with the requirements for multi-regional clinical trials or the national guidelines for the review of natural medicines.

 

*This article was prepared by Longxi Yi from Accestra Consulting providing China Regulatory Affairs Outsourcing for Drugs/Pharmaceutical 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, Excipients and Packaging Materials, ANDA, eCTD submission and others.

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