CFDA releases consistency evaluation application process

On June 9, “Announcement on Matters Concerning the Quality and Efficacy Consistency Evaluation of Generic Drugs (Draft for Comment)” “Guidelines for Acceptance and Review of the Quality and Efficacy Consistency Evaluation of Generic Drugs (Variety for Consistency Evaluation) (Draft for Comments) “Guidelines for Acceptance and Review of Quality and Efficacy Consistency Evaluation of Generic Drugs (Domestic Co-production and Marketed in Europe, America and Japan) (Draft for Solicitation of Comments)” will be posted on the CFDA official website at the same time. The deadline for soliciting comments is July 9.

The contents of the “Announcement on Matters Concerning the Consistency Evaluation of the Quality and Efficacy of Generic Drugs” (draft for comments) are as follows:
Reference preparation

1. In order to facilitate the selection of reference preparations by enterprises, the Food and Drug Administration (Office of Consistency Evaluation) will publish the “Announcement on the Implementation of the “Opinions of the General Office of the State Council on the Consistency Evaluation of the Quality and Efficacy of Generic Drugs”” (Food and Drug Supervision) Announcement No. 106 (2016) of the General Administration of State Administration of China) The attached list of 289 varieties of original-research company drugs is listed and announced to the public for reference when companies choose reference preparations. The list is divided into two categories: listed in China and not listed in China. It is recommended that companies choose one of them as a reference preparation for filing in the following order:
   (1) Original research drugs: imported original research drugs, drugs produced and marketed by original research companies in China, and unimported original research drugs;
   (2) In the case that the original research enterprise ceases production, it is possible to choose drugs that have been approved for marketing in the United States, Japan or the European Union and have obtained the status of reference preparations.
2. All the reference preparations filed by the enterprise to the Food and Drug Administration (Consistency Evaluation Office) are disclosed to the public, and the Food and Drug Administration (Consistency Evaluation Office) will provide guidance on different situations:
   (1) It can be confirmed that it meets the conditions of the reference preparation;
   (2) In doubt;
   (3) Obviously not meeting the conditions.
   Regarding the two cases (2) and (3), whether to continue the research or reselect the reference preparation, the enterprise shall decide on its own and bear the corresponding responsibilities.
3. For the reference preparation products purchased from overseas by the enterprise itself, when submitting the consistency evaluation materials, materials such as proof of purchase, product packaging and instructions shall be provided, or other appropriate methods shall be used to prove that the reference preparation used is the product of the designated enterprise. If the enterprise discovers that the reference preparation product used is a counterfeit product, it shall suspend the ongoing research work and report to the Food and Drug Administration (Drug Review Center); if the supervisory authority finds that the reference preparation product used by the enterprise is a counterfeit product, it shall Relevant enterprises shall be notified in time, the review and approval shall be suspended, and the approval documents shall be revoked and the information shall be disclosed to the public if the listing has been approved, and the enterprises shall be instructed to explain and file investigations according to the situation.

BE test

1. In accordance with the “Several Opinions of the General Office of the State Council on Further Reforming and Improving Policies for the Production, Distribution and Use of Drugs” (Guobanfa [2017] No. 13), implement the filing system for bioequivalence testing institutions. The bioequivalence test in the consistency evaluation can be conducted in an existing accredited clinical trial institution or in other qualified institutions. The sponsor of a bioequivalence trial may hire a third party with evaluation capabilities to evaluate the institution that conducts the bioequivalence trial in accordance with the requirements of the GCP.
2. Prior to the start of the bioequivalence test, the initiator shall, in accordance with the requirements of the “Announcement on the Information Platform for Drug Clinical Trials” issued by the Food and Drug Administration, provide information on the test items, clinical trial institutions, sample analysis institutions, reference preparations, etc. Drug clinical trial registration and information disclosure platform registration of the Drug Evaluation Center of the Food and Drug Administration. Provincial food and drug regulatory authorities strengthen the daily supervision of clinical trial institutions, and promptly report any problems to the Food and Drug Inspection Center of the State Food and Drug Administration.
3. For the varieties that meet the “Guiding Principles for the Exemption of Human Bioequivalence Tests” and the varieties that are not suitable for in-vivo research, the Food and Drug Administration (Drug Evaluation Center) will publish the specific list of varieties in batches and propose Guiding opinions on the consistency evaluation of such varieties.
   Original research and localized varieties
4. The “Guiding Opinions on the Classification of Generic Drugs Quality and Efficacy Consistency Evaluation” The varieties produced and marketed in China by the Zhongyuan Research Company shall be classified according to the following conditions:
   Those that have not undergone major changes after marketing, or those that have undergone major changes after marketing but do not affect the quality and efficacy after review, can be selected as reference preparations after being reviewed and verified by the Food and Drug Administration.
   If there is a major change after listing and the quality and efficacy of the same product in the country of origin are different, the enterprise shall issue a statement to the society within 30 days of this announcement, explaining the difference and the reason, and conduct a consistency evaluation as required.
   Varieties declared according to the principle of consistency
5. For products declared and reviewed according to the principle of consistency of quality and efficacy of the original drug before marketing, the manufacturer should evaluate whether it meets the requirements of the current technical guidelines for the quality and efficacy of generic drugs. After the evaluation meets the requirements, the manufacturer can apply to the Food and Drug Administration (Drug Evaluation Center) for exemption from participating in the consistency evaluation, and submit the original registration application materials and bioequivalence test data to the Food and Drug Administration ( Drug Evaluation Center). The review of the consistency evaluation materials submitted based on the original registration application materials focuses on reviewing the authenticity and completeness of the original materials and clinical trial data. If the assessment fails to meet the requirements, a consistency assessment shall be conducted as required.
   For generic drug registration applications that are under review according to the registration classification of the original chemical drug, the applicant may submit an application to the Food and Drug Administration for review according to standards consistent with the quality and efficacy of the original drug. Those who pass the review shall be deemed to have passed the consistency evaluation.
   European, American and Japanese listed varieties
6. To support the listing of drugs produced by domestic enterprises in the EU, the United States or Japan that are approved for marketing in China.
   (1) If a generic drug approved to be marketed in the EU, the United States or Japan has been marketed in China and produced using the same production line and the same prescription process, the applicant shall submit the bioequivalence study, pharmaceutical research data and other technical materials for the overseas listing application. The Food and Drug Administration (Drug Evaluation Center) allows them to use the labels that have passed the consistency evaluation after the review, and enjoy the relevant policies for passing the consistency evaluation.
   (2) If a generic drug approved for marketing in the EU, the United States or Japan has been marketed in China but adopts different production lines or inconsistent prescription processes, the company shall follow the requirements of consistency evaluation to study the prescription process and bioequivalence reported for overseas listing Submit a change application to the Food and Drug Administration (Drug Evaluation Center) for technical data such as pharmaceutical research data. After the review is passed, the prescription process is approved to be changed, and it is allowed to use the logo that has passed the consistency evaluation and enjoy the relevant policies for the consistency evaluation. .
   (3) Those listed in the EU, the United States or Japan but not listed in China, and clinical studies have confirmed that there is no ethnic difference, they can use the bioequivalence studies and pharmaceutical research data submitted for overseas marketing to report to the Food and Drug Administration (Drug Review Center) submit a marketing application; if there may be ethnic differences, corresponding clinical trials should be carried out.
   (4) The above-mentioned bioequivalence data, pharmaceutical research data and other technical data should be research data used to apply to the European Union, the United States or Japan for listing, and should meet the requirements of China’s current technical guidelines and be accepted by the Food and Drug Administration scene Investigation. Where false certification documents, materials, samples or other deceptive means are provided to obtain drug approval certification documents, the approval certification documents shall be revoked.
   The drugs mentioned in the preceding paragraph include the cases where they are produced in China and listed in the name of a controlling subsidiary company established or acquired overseas. For enterprises established overseas with investment or equity participation or holding by Chinese citizens, the drugs produced overseas shall still apply for marketing authorization as imported drugs.
   Consistency evaluation report
7. When an enterprise submits an application for consistency evaluation, the technical research department to which the applicant belongs or the commissioned drug inspection agency, third-party agency, etc. shall issue a sample inspection report, which shall be submitted to the Food and Drug Administration as one of the application materials. The Food and Drug Administration will publish a list of institutions with drug quality review capabilities on relevant websites.
8. The Drug Evaluation Center of the General Administration of Food and Drug Administration set up a compliance office to coordinate relevant links such as cause inspection, random inspection, and review, to improve the quality and efficiency of inspection, inspection and review, and to ensure that inspectors and reviewers follow The same standard is used to check and review the application for consistency evaluation drugs. The review, verification and inspection shall be carried out in accordance with the relevant regulations of the Food and Drug Administration and recorded in the relevant drug files. The review, verification and inspection staff shall be responsible for the relevant conclusions.
9. The applicant shall bear all legal responsibilities for the data declared. If there are any problems with the authenticity of the application materials found in the evaluation process of the various drugs mentioned in Articles 7, 8, 9, and 10, the application will not be approved, and the Food and Drug Administration (Inspection Bureau), together with the Food and Drug Inspection and Inspection Center, will file a case for investigation according to law , Revoke the original drug approval number, and investigate the legal responsibility of the responsible person. If there is a completeness problem in the application materials, the application will not be approved, and the applicant can return to the application to complete the application again.
10. Since the date of the announcement, applications for the consistency evaluation of the quality and efficacy of generic drugs shall be accepted or received by the Acceptance and Reporting Center of the Food and Drug Administration.
    (1) For generic drugs (including imported generic drugs) that have changed the prescription process, a supplementary application should be submitted with reference to the relevant requirements of the “Administrative Measures for Drug Registration”, and the special declaration items in the application form should indicate “consistency evaluation application, prescription process There are changes”. The application materials for domestic generic drugs shall comply with the Announcement on Matters Concerning the One-time Import of Reference Drugs for Research in the Development Process (Announcement No. 120 of 2016 of the General Administration of Food and Drug Administration), and the Announcement on the Publication of New Registration Classification of Chemical Drugs. (Trial) Circular” (CFDA Circular 2016 No. 80) information requirements. Imported generic drugs can submit application materials in accordance with the requirements of Circular 120 or Circular 80 of 2016; they can also follow the full set of overseas technical materials of CTD specified by ICH and the “summary” part required by Circular 120 of 2016.
    (2) For the consistency evaluation application that does not change the prescription process, the supplementary drug application form should be filled out, and the “consistency evaluation application, the prescription process has not been changed” should be indicated in the special declaration of the application form. The application materials shall meet the requirements of item (1) of this article or relevant notices and announcements.
    (3) Generic drugs produced in China that are approved to be marketed in the EU, the United States or Japan are already on the market in China and are planned to be produced on the same production line and the same prescription process as the overseas listed drugs, a supplementary drug application form should be filled out, and the application form specifically states The items indicate “application for consistency evaluation of the same production line, the prescription process has changed” or “application for consistency evaluation of the same production line, the prescription process has not been changed”. The application materials shall meet the relevant requirements of Item 10 of this announcement.
    (4) Within 5 days after the acceptance and reporting center of the General Administration of Food and Drug Administration sign for the materials, the Drug Evaluation Center will conduct a formal review of the application materials. If the requirements are met, the acceptance and reporting center will issue an acceptance notice (with changes to the prescription process) or accept Notice (the prescription process has not been changed); if the requirements are not met, a notice of rejection (the prescription process has been changed) or a notice of rejection (the prescription process has not been changed) shall be issued, and the reasons shall be explained.
    Consistency evaluation review
11. After acceptance, the Drug Evaluation Center of the State Food and Drug Administration will conduct a file review of the enterprise application materials. Those that meet the requirements shall be filed within 45 days; those that do not meet the above requirements shall not be approved and the reasons shall be explained.
    The Drug Evaluation Center of the Food and Drug Administration puts forward the need for inspection and random inspection based on the filing review. The Food and Drug Inspection Center of the Food and Drug Administration uniformly organizes the inspection or inspection of the research site, production site or clinical trial data. sampling. If inspection is required, the relevant inspection agency shall be designated. The applicant shall ensure that the quality and curative effect of the sample tested are consistent with those of the tested samples described in Article 11 of this announcement. The inspection work for reasons is generally completed within 60 days after the completion of the filing review.
12. The Drug Evaluation Center of the General Administration of Food and Drug Administration summarizes the inspections and sample inspections, and proposes a comprehensive review opinion on whether the consistency evaluation is passed. Approval documents will be issued by the Drug Evaluation Center of the Food and Drug Administration and included in the “List of Listed Drugs in China”, allowing them to use labels that have passed the consistency evaluation and enjoy the relevant policies for passing the consistency evaluation.
    The review work should generally be completed within 120 days after acceptance. If it is deemed necessary for the applicant to supplement the information after review, the applicant shall complete the supplementary information in one go within 40 days.
    Public review conclusion
13. The application for consistency evaluation of the enterprise declaration, and the evaluation conclusions are all open to the public. For products that have passed the consistency evaluation, the product specification, enterprise research report, and bioequivalence test data are disclosed to the public, and technical secrets such as the production process and parameters of the enterprise are involved, in accordance with the relevant regulations of the Food and Drug Administration. The specific standards shall be separately stipulated by the Center for Drug Evaluation of the Food and Drug Administration. For varieties that have not passed the consistency evaluation, the reasons for rejection will be explained at the same time as the decision of rejection is announced.
14. If the comprehensive review conclusion of the consistency evaluation is not passed, the Drug Evaluation Center of the Food and Drug Administration shall inform the enterprise. If the enterprise has different opinions, it may apply for meeting communication and submit written opinions within 15 days from the date of publication of the relevant conclusions (or notify the applicant). The Center for Drug Evaluation of the Food and Drug Administration shall make a decision on whether to hold a meeting within 15 working days after receiving the application and notify the applicant in writing. Applicants must prepare written comments and deliver them to the Drug Evaluation Center of the Food and Drug Administration within 20 working days before the meeting. The Center for Drug Evaluation of the Food and Drug Administration shall hold a communication meeting within 20 working days after receiving the written opinion of the applicant.
    If the company still has objections after communication, it may apply to the Drug Evaluation Center of the Food and Drug Administration to convene an expert advisory committee for public demonstration. The Center for Drug Evaluation shall make an opinion based on the conclusion of the expert’s evaluation and report to the Food and Drug Administration for a decision. The methods and procedures for the convening of the expert advisory committee shall be implemented in accordance with the relevant regulations of the Food and Drug Administration.

Ensure supply

1. If there are more than 3 manufacturers of the same type of drugs that have passed the consistency evaluation, the products that have not passed the consistency evaluation will no longer be selected for centralized drug procurement. After the first product passed the consistency evaluation, it will no longer accept applications for the consistency evaluation of the same product from other drug manufacturers after three years.
   For the national essential drug catalogues that affect the market supply due to the small number of manufacturers that have passed the consistency evaluation, the Food and Drug Administration in conjunction with relevant ministries and commissions will issue a list to encourage companies to develop and declare generic drugs. The list of medicines will be dynamically adjusted based on the passing of the variety consistency evaluation.
   The Food and Drug Administration encourages companies with the qualifications of marketing license holders to entrust the production of drugs that have passed the consistency evaluation to other manufacturers in order to expand production and meet market needs.

other

1. The staff of the food and drug regulatory authority shall be obliged to keep confidential the technical and commercial secrets in the application documents of the enterprise and the process of drug review and inspection. If there is evidence to prove that food and drug regulatory staff leaked enterprise technical and commercial secrets, they will be dealt with in accordance with the relevant regulations of the Food and Drug Administration for confidential management; suspected crimes will be transferred to judicial authorities for criminal responsibility. External reviewers and inspectors who perform temporary work tasks must sign a confidentiality agreement. Any violation of the confidentiality agreement shall be dealt with in accordance with the provisions of the agreement.
2. The Food and Drug Administration encourages all sectors of the society to supervise the drug R&D and production behaviors of the company’s consistency evaluation of drugs and report illegal acts. Encourage all sectors of society to supervise drug review and inspection activities. The whistleblower is kept confidential and rewarded in accordance with relevant regulations.