Accestra Consulting’s Zhao Lu* looks back on a year in which China’s Center for Disease Evaluation (CDE) rejected a record-breaking number of drug applications, explores some of the main reasons behind these rejections, and suggests how applicants can avoid them in future.

 

In 2021, China’s Center for Disease Evaluation (CDE) rejected 542 drug applications compared with 367 rejections in 2020 equating to an almost 50 percent increase in rejections.

From the 542 rejected drug applications, 359 were due to failure to submit supplementary dossiers in time (hereinafter “Exceed Deadline”), accounting for 66.3 percent of all rejected applications.

  • 349 were chemical drugs, nine were Traditional Chinese Medicines (TCMs), and one was a biological product

The remaining 183 applications were rejected for reasons related to safety, efficacy, quality, and others (hereinafter “Defective Cases”).

  • 126 were chemical drugs, 43 were biological products, and 14 were TCMs (see the chart below).

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The major problems identified by CDE are as follows:

  1. Insufficient Information and Feasibility

This problem exists mainly in the early phase of developing drugs (IND phase) and certain generic drugs as well as supplementary applications. The issues primarily occurred in the following aspects:

  • Unclear clinical position of drug R&D
  • Unreasonable selection of indication
  • Unreasonable choice of dosage form or route of administration
  • Ineffective drug suggested by existing research data
  • An Ambiguous target of action and mechanism, etc

 

  1. Drug Efficacy Issues

  • The clinical study data provided could not demonstrate the efficacy of the drug
  • Issues related to the clinical trial protocol or study quality control, resulting in the invalidation of the effectiveness of the tested drug indication
  • The results of the bioequivalence (BE) test of generic drugs showed no equivalency to the reference listed drug (RLD)
  • Lack of clinical data for Chinese ethnic groups

 

  1. Drug Safety Issues

  • Early IND phase findings suggest that the toxicity is significant, or the safety risks are too high to justify further clinical development
  • Issues with the pre-clinical safety study methods or study quality control issues, or insufficient study data to support subsequent clinical development
  • The existing clinical study data shows serious adverse reactions, and the ratio of clinical benefit versus risk is unreasonable
  • Lack of safety clinical data in Chinese ethnic groups

 

  1. Quality Control

Serious defects in pharmaceutical research

  • Inconsistency of quality of RLD
  • Inconsistency of study samples tested at each development stage
  • Failure to meet the Chinese technical requirements for the marketing of generic drugs
  • Failure to use APIs of legitimate origin as required
  • Non-conformity of testing samples according to the Chinese regulations

 

  1. Regulatory Compliance

A very significant reason for rejecting drug application is due to regulatory gaps and failure to comply with China NMPA requirements including but not limited to the following three aspects:

  • Data gaps according to the Chinese requirements
  • Major defects affecting product quality found
  • Disqualification during sampling inspection

 

  1. Other problems

  • Failure to provide the necessary data or supplementary materials as requested by CDE
  • Lack of necessary content found during the technical review

 

The top two suggestions for avoiding drug rejections with CDE are as follows:

  1. Comply with China’s Regulatory Requirements

  • It is crucial to submit the required materials in time and to catch up with all deadlines
  • It is advised to conduct thorough regulatory compliance assessments and gap analyses of the dossiers so as to minimize the probability of being rejected

 

  1. Attach sufficient importance to the basis of drug development

  • Drug development and registration should be based on the clinical needs and  size of the Chinese market. Special attention should be paid to solving unmet clinical needs
  • Clinical value should be put in the leading position. Full attention should be paid to the advantages of similar innovative drug development and to avoiding grouping, low-level and repetitive innovation

 

*  This article was prepared by Accestra Consulting which provides China Regulatory Affairs Outsourcing for Pharmaceutical drugs, 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, Excipients and Packaging Materials, ANDA, pharmacovigilance services and others.

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