Comparison of the Requirements of 'Chemical Drug Registration Classification and Application Materials'

On April 30th, NMPA and CDE issued a series of nearly 30 drafts for comments. After reading the "Chemical Drug Registration Classification and Application Information", the editor of the Yeedozencom Registration Department make a simple comparison between the “Announcement of the Work Plan for the classification reform of chemical Drug registration”, (No. 51, 2016) which released by the State Administration for Market Regulation. This time, the drafts mainly have the following changes:

1, Category 1 and category 2 are basically unchanged.

2、Category 3 and category 4 generics have been changed from the requirement to be consistent with the quality and efficacy of the "original research drug" to the quality and efficacy of the "reference preparation". It should be noted that: with sufficient research data to prove rationality, the specifications, usage and dosage of category 3 generic drugs may be inconsistent with the reference preparations. Under the premise of not changing the usage and dosage, it is reasonable to increase the specifications of the reference preparation for the convenience of clinical use; but the differences in usage and dosage seems to be similar to improved new drug.

3. Category 5.1 is clearly defined as new drugs and improved new drugs that have been marketed overseas, and has put forward the requirements of "obvious clinical advantages" for improved drugs. Since the concept and connotation of Chinese improved drugs are not consistent with those of foreign countries, this may mean that even if the improved new drugs are marketed in Europe and America, they may not be able to be marketed in China.

4. Category 5.2 Compared with trial implementation, overseas-produced generic drugs that are allowed to be developed simultaneously at home and abroad do not need to provide certification documents that overseas regulatory agencies allow drugs to be marketed when applying for clinical trials. However, according to the definition of category 5.2, the application for listing still needs to be approved abroad, which is meaningless for the vast majority of category 5.2.

5. Delete relevant regulations during the monitoring period. The promulgated "Administrative Measures for Drug Registration" and the supporting documents for soliciting opinions currently do not involve provisions on intellectual product protection and administrative protection such as patents, data protection, monitoring period, etc., waiting for follow-up documents.

6. The relevant requirements of this revision include the relevant content of the policy interpretation issued since the implementation of the new registration classification of chemical drugs in 2016. For example, a compound with a brand-new ingredient is declared as category 1, a domestically produced drug adds an overseas approved and in China unapproved new indication is declared as category 3, and an original drug that has been marketed in China adds an overseas newly approved indication is declared as category 5.1.

7. It is clarified that during the review and approval period of drug marketing applications, drug registration classification and technical requirements will not change due to the approval of preparations with the same active ingredients in domestic and foreign markets. Does this mean that the final registration classification is determined when the marketing authorization application is submitted, and the previous registration classification may change with the approval of the same variety at home and abroad?

8. The ICH and CTD format rules the world. All chemical drug applications need to be submitted in this format. An upgraded version of Document 80 is under development.

Annex 1-1

Classification of chemical drug registration and requirements for application materials

(Draft for comments)

1. Classification of Chemical Drug Registration

The chemical drug registration classification is divided into innovative drugs, improved new drugs, generic drugs, and overseas listed but domestic unlisted chemical drugs, which are specifically divided into the following five categories:

Category 1: Innovative drugs that have not been marketed both at home and abroad. Refers to drugs that contain new compounds with clear structures and pharmacological effects and have clinical value.

Category 2: Improved new drugs that have not been marketed both at home and abroad. Refers to a drug optimize its structure, dosage form, prescription technology, route of administration, indications, etc. on the basis of known active ingredients and with obvious clinical advantages.

2.1 Optical isomers containing known active ingredients prepared by resolution or synthesis methods, or esters to known active ingredients, or salts to known active ingredients (including salts containing hydrogen bonds or coordination bonds), or change the acid radicals, bases or metal elements of known salt active ingredients, or form other non-covalent bond derivatives (such as complexes, chelates or inclusion compounds), and have obvious clinical advantages.

2.2 New dosage forms containing known active ingredients (including new drug delivery systems), new prescription technology, and new routes of administration, and have obvious clinical advantages.

2.3 New compound preparations containing known active ingredients, and have obvious clinical advantages.

2.4 Drugs for new indications containing known active ingredients.

Category 3: Drugs that domestic applicants imitate the original drugs that are marketed overseas but have not been marketed in China. Such drugs should be consistent with the quality and efficacy of the reference preparation.

Category 4: Drugs that domestic applicants imitate the original drugs that have been marketed in China. Such drugs should be consistent with the quality and efficacy of the reference preparation.

Category 5: Drugs listed overseas apply for domestic listing.

5.1 The original research drugs and modified drugs that are marketed overseas apply for listing in China. Improved drugs should have obvious clinical advantages. [1]

5.2 Generic drugs listed overseas apply for domestic listing.

The original research drug refers to the first drug approved for marketing at home and abroad, and has complete and sufficient safety and effectiveness data as the basis for marketing.

Reference preparations refer to reference drugs that have been evaluated and confirmed by the NMPA used in the development of generic drugs.

Relevant registration management requirements

(1) Category 1 chemical drugs are innovative drugs, which should contain new compounds with clear structures and pharmacological effects, and have clinical value, excluding the improved new drugs in category 2.1. A new compound preparation containing a new compound with a clear structure and a pharmacological effect shall be declared as category 1 chemical drugs.

(2) Category 2 chemical drugs are improved new drugs, which is optimized on the basis of known active ingredients and should have obvious clinical advantages over its pre-improvement. Known active ingredients refer to the active ingredients of drugs that have been marketed domestically or overseas. If such drugs meet the requirements of multiple situations at the same time, they must be explained at the time of application.

(3) Category 3 chemical drugs are domestically produced imitations that have been marketed overseas and have not been marketed in China. They have the same active ingredients, dosage forms, specifications, indications, administration routes, usage and dosages as the reference preparations, and the quality and efficacy have been proven consistent with the reference preparation.

In the case of sufficient research data to prove its rationality, the specifications, usage and dosage may be inconsistent with the reference preparation.

(4) Category 4 chemical drugs are domestically produced drugs that are imitations of domestically marketed original drugs, which have the same active ingredients, dosage forms, specifications, indications, routes of administration, usage and dosage as the reference preparations, and the quality and efficacy are proven consistent with the reference preparation.

（5) Category 5 chemical drugs are drugs that are listed overseas and apply for listing in China. Category 5.1 chemical drugs are original research drugs and modified drugs. The modified drugs are optimized on the basis of known active ingredients and should have obvious clinical advantages over those before the modification; category 5.2 chemical drugs are generic drugs, and the quality and efficacy of generic drugs should be consistent with the reference preparations. The overseas-produced generic drugs that are developed simultaneously at home and abroad should be declared as category 5.2 chemical drugs. For clinical trials, documents that permit the drug to be marketed and sold are not required.

(6) The drugs produced in China add indications that have been approved overseas and not approved in China shall be declared as category 3 chemical drugs. For overseas original research drugs that have been marketed in China, the additional indications that have been approved overseas and not approved in China shall be declared as category 5.1 chemical drugs.

(7) During the period of review and approval of drug marketing applications, drug registration classification and technical requirements shall not change due to the approval of preparations with the same active ingredients in domestic and overseas markets.

3. Requirements for application materials

(1) Applicants submitting drug clinical trials, drug marketing registration and chemical raw material drug applications shall conduct research in accordance with the relevant requirements of the relevant technical guidelines published by the national drug regulatory authority, and organize and submit the application materials in accordance with the current version of "M4: General Technical Document for Registration Application of Human Drugs (CTD) " (hereinafter referred to as CTD) format number and item sequence. Inapplicable items may be reasonably missing items, but they should be marked as inapplicable and the reasons should be explained.

(2) The applicant shall submit the clinical trial database in CD form on the basis of CTD when completing the clinical trial and submitting the application for drug marketing registration. Please refer to the relevant guidelines for clinical trial data submission for specific requirements such as database format and related documents.

(3) The Center for Drug Evaluation of the NMPA will update the CTD documents in a timely manner and publish them on the center's website in accordance with the needs of the drug review work, combined with the revision of the ICH technical guidelines.