China Reference Listed Drugs (RLD) application requirements for Chemical Generic Drugs was issued by the Center for Drug Evaluation (CDE) in October 2020. This is of particular interest following the recent National Medical Products Administration (NMPA) announcement on the Detailed registration application material requirements for transferring chemical drug registrations from produced abroad to Made-in-China earlier this year, which simplified registration criteria for generic drugs include self-testing of 1-3 batches and stability studies on 1-3 batches. Below we present the key requirements for the application dossier.
Generic Reference Listed Drugs (RLD) are specific formulations of pharmaceuticals used as benchmarks in the evaluation and approval of generic drugs. These reference preparations ensure that generics meet established standards for safety, efficacy, and quality, providing a basis for comparison during the regulatory review process.
The selection and approval process for these reference preparations involves detailed requirements and evaluations as outlined below, which also incorporated information from China’s Announcement on Procedures for Selection and Determination of RLD for Chemical Generic Drugs (No. 25 of 2019).
1. Application Review of the RLD
(1) Basic Information of the Variety
- Generic Name of the Drug: The common name used for the drug.
- Active Ingredient: The specific chemical component that provides the therapeutic effect.
- Dosage Form and Specification: The form in which the drug is administered (e.g., tablet, injection) and its dosage.
- Brief Description of Indications: The medical conditions or diseases the drug is intended to treat.
- Inclusion in Pharmacopoeias: Information about the drug’s inclusion in official drug compendiums of various countries, with publication dates or version numbers.
- Release/Publicity of Reference Preparations: Whether the reference preparation has been released by the State Drug Administration, detailed in a published catalog.
Variety Original Research Information
- Original Research Clarity: Whether the original research behind the drug is well-documented, including details like the research company, listing time, and earliest listing country.
- Clinical Safety and Effectiveness: Summary of pre-market and post-marketing clinical research
(2) Basis for the Application of the Reference Preparation
- Reasons for Applying: Justification for the application, especially if no reference preparation has been released or if there are objections to the existing ones.
- Original Research Status: Whether the proposed reference preparation is an original research product and details about its licensee and source.
- Safety and Efficacy Data: Whether there is sufficient safety and efficacy data for the proposed reference preparation.
- Quality Control: Whether the quality of the proposed reference preparation meets international technical requirements.
- Accessibility: Evidence showing the availability and accessibility of the proposed reference preparation.
- Comparison in Prescription: Comparison of prescriptions in different countries to analyze the impact of prescription differences on drugs.
- Indications Consistency: Comparison of approved indications in different countries to ensure they are consistent.
2. Research Information
(1) Domestic and Foreign Ratifications
- Domestic Listing: Approval status of both original and generic drugs in the home country.
- U.S. Listing: Inclusion in the FDA Orange Book and other relevant listings.
- Listing in Europe: Approval status within the European Medicines Agency (EMA) and national agencies.
- Listing in Japan: Approval status within the Japanese Pharmaceuticals and Medical Devices Agency (PMDA).
- Other Countries: Approval status in additional countries if applicable.
(2) Domestic and Foreign Use
- Usage and Dosage Comparison: Comparison of indications, usage, and dosage across different countries.
- Other Drugs with Same Indication: Overview of other drugs with the same indication as the reference preparation.
- Prescription Comparison: Comparison of the composition of prescriptions approved in various countries.
- Safety Warning Information: Compilation of safety warnings from drug regulatory authorities in different countries.
3. Selection and Determination Procedures
(1) Evaluation Criteria
- Original Drug Standards: Evaluation of the original research and clinical data to establish benchmarks.
- Manufacturing Consistency: Ensuring the reference drug’s manufacturing process is consistent and meets quality standards.
- International Standards: Verification that the reference drug complies with international regulatory standards.
(2) Review Process
- Submission of Documentation: Detailed documentation must be submitted, including clinical data, manufacturing information, and quality control data.
- Expert Panel Review: An expert panel evaluates the submitted documentation against established criteria.
- Public Consultation: A period for public comments and objections is provided to ensure transparency and address any concerns.
(3) Final Determination
- Approval and Listing: Once approved, the reference drug is listed in official catalogs and made available for generic drug comparison.
- Monitoring and Updates: Continuous monitoring and periodic updates to the reference drug list to reflect new research and regulatory changes.
4. RLD Selection Principles
The RLD selection principles stipulated in the announcement (No. 25 of 2019) are as follows:
(1) Original Drug Priority
- In Principle: The RLD should be an original drug.
- Priority Sequence:
- Domestic Approved Original Drugs: Priority is given to original drugs approved in China.
- Approved Drugs Produced in China by Foreign Original Drug Companies: Includes those produced in China through technology transfer.
- Original Drugs Not Imported: Original drugs that have not been imported.
(2) Alternatives When Original Drug is Unavailable
- Terminated Production or Quality Issues: If the original drug has terminated production or is not suitable as the RLD for quality reasons, companies can choose:
- Internationally Recognized and Approved Drugs: Products approved in the United States, Japan, or EU countries.
- Internationally Recognized and Produced in China: Products produced or technically transferred for production in China that are recognized internationally.
(3) Other Controllable Drugs
- NMPA Evaluation: Other drugs whose safety, efficacy, and quality are controllable after evaluation by the National Medical Products Administration (NMPA).
5. Links to Research Information Websites
Provision of URLs to access domestic and international marketing information of the proposed reference preparation.
6. Annexes
Additional supporting documents including self-check forms, declarations of authenticity, accessibility proofs, instructions, and relevant clinical research information.
7. Fill in the Instructions
Guidelines for completing the application, including the importance of maintaining the structure and numbering of the document.
This structured approach ensures that the selection of reference preparations for chemical generics is thorough and based on comprehensive evidence, thereby maintaining high standards for generic drug approvals, in line with China’s regulatory procedures.
Further information
Read the original article on China Reference Listed Drugs application requirements for Chemical Generic Drugs.
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