How to "go to Beijing to take the test" for a drug marketing authorization application?

"From submitting the application for marketing authorization 'going to Beijing to take the test' to obtaining the approval document 'Golden List Title', it is the joy of the applicant after the arduous process of trying to meet the clinical drug nee.

Written by | Zhu Lin

Director of Registration Department of Hengrui Medicine

A registration applicant submits an application for a drug marketing authorization, just like a student who has been studying hard for many years in a cold window, and finally comes to Beijing to take the ex.

CDE publishes an annual review report every ye.

Under the new "Administrative Measures for Drug Registration", there are new procedural requirements for marketing authorization applicatio.

❖ Integrating the culmination of reforms and solidifying procedur.

❖ Uniform procedural requirements apply to different marketing authorization applications for new drugs and generic dru.

The general listing application registration process flow is as follows:

There are many notable links in the implementation of the "Administrative Measures for Drug Registration" and the registration procedures issued and implemented in 202 Next, we summarize and discuss some matters in the marketing authorization application proce.

Acceptance review stage

In order to cooperate with the implementation of the "Administrative Measures for Drug Registration", China's drug regulatory authorities have issued guidelines for the acceptance and review of various registration applications to guide the work of drug registration applicatio.

Determination of drug registration classification

Drug registration classification is a tool for classifying management of various drug registration matters, and is the identity certificate for registration applicatio.

In the practice of registration, some special circumstances may easily lead to questions about the registration classificati.

The concept of "global new" represents a new height of scientific development of drug supervision in Chi.

1 The "global new" concept of innovative drugs first emphasizes the innovativeness of innovative dru.

(1) In practice, compounds that are marketed as medical devices overseas and are applied for listing as drugs in China cannot be regarded as innovative drug.

2 The classification of improved new drugs has high requirement.

(1) Determination of "improved drugs" The determination of modified drugs directly affects the basis for the classification of improved new drugs, and it is usually necessary to select the optimal preparation of the same active ingredient for comparis.

According to the author's understanding of the current registration regulations, the improved drug may be either domestically or overseas, and it is dynam.

The same active ingredient and similar products may continue to be approved for marketing by various regulatory authorities around the wor.

Therefore, an improved new drug may be approved by the same type of drug, resulting in a change in registration classification, falling into an embarrassing situation where it is neither an innovative drug nor an improved new drug, and does not meet the technical requirements of generic dru.

This poses a huge challenge to the adoption of the "Fast Follow" project R&D model, which is common in the field of innovative drugs, for improved new dru.

Therefore, it is necessary to be cautious in determining such registration and research strategies, especially for special preparation technology drugs such as sustained and controlled release preparations, microspheres, and liposom.

During clinical trials, the pharmacy adopts the development and design of improved new dru.

It needs to be overturned and re-develop.

(2) The announcement of the "Technical Guiding Principles for Clinical Trials of Improved New Drugs of Chemical Drugs" on the issue of obvious clinical advantages , to a certain extent, shows the systematic discussion of the "obvious therapeutic advantages" by the regulatory authorities to the industry, and also conveys The domestic improved new drug requirements are different from the well-known US FDA 505b(2) registration pathw.

Depending on the size of the clinical advantage, the question of whether to improve the field of "big change" or "small change" is expected to exist for a long ti.

The requirements for obvious clinical advantages are sometimes not easy to understa.

For example, between the two dosage forms of oral solid preparations, "orally disintegrating tablet" and "orally dissolving film", which one has more clinical advantages, the change from oral disintegrating tablet to oral dissolving film is a "big chang.

Or a "small change"? Judging from the improved oral dissolving film preparations launched in 2021, the clinical advantages of oral dissolving film preparations of some active ingredients have been recogniz.

Registration of chemical raw materials

At present, for the marketing application of domestic chemical drugs, chemical raw materials need to be registered and filed, and they cannot be declared in the preparation materia.

The registration application form of the preparation needs to fill in the registration number and acceptance number of the API, so it takes time to complete the acceptance of the registration and filing of the API before filling in the registration application form for the preparation to declare the preparati.

The main body of the registration of chemical raw materials is the production enterpri.

If the registration applicant uses CMO to produce chemical raw materials for registration and declaration, they need to agree on more detailed terms in the commercial contract, such as market supply, integration of application materials, and engravi.

The specific method of disk submission and the follow-up review information sharing,e.

China's "Original and Auxiliary Package Registration Platform" has been under construction, and various management measures are more in line with the expectations of applicants and the publ.

It is expected that the platform will be mature and stable, and its functions will be gradually launched to jointly serve the drug review and approval syst.

Submission of Confidential Information

In the application for drug marketing authorization such as cooperative development, introduction of products or imported products, there is inevitably the problem of confidential informati.

These materials need to be provided to the regulatory authorities, but may not be suitable for all registration applican.

Generally speaking, overseas TPC companies usually only provide some public information to the preparation applicant, so the submission of the preparation marketing application involves the submission of the supplier's confidential informati.

Formulation of process information sheets and quality standards (or inspection procedures)

In the registration procedure, the registration site inspection and registration inspection are carried out in parallel with the technical revi.

The process information sheet and quality standard are important documents for registration verification and registration inspecti.

They are provided by the applicant and have not been reviewed by the review department in advan.

The normative, scientific and completeness of the document is the responsibility of the applica.

(1) The content of the process information table is derived from the CTD M3 data, and there are also some daily GMP control conten.

Generally speaking, the process information table formulated by the registration applicant may not be so detailed, and it will be long-term in terms of parameter description and quality control limi.

There is room for commercial producti.

This may not be completely consistent with the technical review requirements, and as a registrar, two-way communication and balance are requir.

Overly detailed process information sheets are challenging for both regulators and applicants to manage chang.

Relevant information may change during the review and approval process, such as minor changes in the included reagents, internal control testing equipment, e.

, corresponding documents and assessments should also be prepared and updated during the technical review proce.

(2) Attention should be paid to accuracy and consistency in formulating the process information tab.

The process information table is a highly condensed pharmaceutical research data, and its formulation and revision is a complex project that requires the participation of multidisciplinary professionals in pharma.

The process information table is generally regarded as a relatively high level of confidentiality docume.

How to meet the requirements of confidentiality and information sharing, and to ensure the accuracy, integrity and consistency of the process information table with the CTD M3 data, is a test of the applicant's manageme.

Errors in the details of the process information sheet may lead to unnecessary verification defec.

(3) The quality standard needs to meet the requirements of the "Chinese Pharmacopoeia" and the drafting of the process information sheet has opportunities for rectification and updating if it causes on-site inspection defec.

In contrast, the problems caused by the normative quality standards may be more serio.

The drafting of quality standards must comply with the >

Issues in the review and approval process

Common Name Approval

According to the regulations, the approval of the generic name of the drug must be submitted together with the application for marketing authorizati.

Therefore, during the review and approval process, the generic name of the drug shall be subject to the naming letter issued by the State Pharmacopoeia Commissi.

The official naming letter needs to be obtained in time, which will not affect the subsequent review and approv.

In fact, the Chinese generic name of the drug may have been confirmed by the State Pharmacopoeia during the research and development process according to the corresponding translation method of the WHO (World Health Organization) INN (International Non-Proprietary Drug Nam.

People issue naming lette.

The State Pharmacopoeia Commission will publicize the translated WHO INN generic names in batches for commen.

Coordination of on-site inspection, registration inspection and technical review

Registration verifications and registration inspections come in various forms, and there are also various repor.

These reports need to be provided to the review body for technical revi.

Therefore, to coordinate on-site registration inspection, registration inspection and technical review procedures, it is first necessary to ensure that reports related to inspection and inspection can enter the review system of the review institution in a timely mann.

Registration on-site verification is usually divided into research and development on-site verification and production on-site verificati.

Research and development on-site verification is divided into pharmaceutical research, preclinical research and clinical trial data verification according to specialti.

The pharmaceutical research and development site inspection is generally combined with the production site inspection, and is also carried out simultaneously with the on-demand GMP compliance inspecti.

Registration inspection includes sample inspection and standard revi.

In the registration process, it is usually pre-inspection, post-acceptance registration inspection, registration inspection during the review process (usually single-item review of written supplementary requirements), and cause-based inspecti.

The inspection and inspection documents during the acceptance and review process are shown in the following table:

After the verification report and inspection report are submitted to the review agency, the registration of the review agency will generate a "registration time", and after the official acceptance, there will be a "reception time", which usually takes 1 to 5 days, and the API may appear longer due to the registration syst.

Time not received, it is worth following close.

During the technical review process, the registration applicant needs to rectify the defects of the on-site inspection, study and improve the quality standard review opinions, and maintain good communication with the review agen.

After the on-site inspection report is transferred to the review agency, CDE specifically initiates the corresponding review to form the review report of the on-site inspecti.

This process may be completed in the professional review of the technical review, or may be restarted after the comprehensive revi.

Professional revi.

The registration inspection has corresponding procedures, time limit and technical requirements, which needs to be completed by the statutory inspection agency with the cooperation of the registration applicant, and is not completely controlled by the registration applicant, which may affect the review time lim.

In the process of issuing the supplement in writing, if a registration inspection occurs, it is likely to affect the approval plan of the registration applicati.

Under the influence of the epidemic, the registration inspection of imported drugs is extremely uncertain in terms of customs clearance of inspection samples, domestic and overseas communication, e.

, many of which have become speed-limiting steps for revi.

Registration inspection is a key factor that must be considered when developing a registration strategy and listing pl.

rolling commit

Rolling submission is a process specific to registration applications that are included in the Priority Review and Approval proce.

Rolling submissions initiated by the applicant may result in an extension of the review time lim.

There are roughly four cases:

(1) Rolling submission agreed in advance with C.

Some clinical trials will be divided into different stages, such as core phase and extension pha.

Through communication procedures, an agreement with the review agency is reached in advan.

After a certain stage is completed, the applicant can submit a marketing authorization applicati.

, in the review process, follow-up data submission can be achieved through professional inquiry letters during the review, electronic submission of the "Applicant's Window", referring to the written supplementary procedures, and submitting written supplementary materials from the acceptance departme.

(2) The rolling submission required by CDE has some supporting da.

CDE may assess that if it is not necessary to go through procedures such as written supplementary, it may be required to submit it by email, professional inquiry letter, "Applicant Window" electronic submission, e.

as a supplement to the formal technical revi.

(3) Submission of regular follow-up stability After the application for marketing authorization is submitted, the applicant will accumulate longer-term follow-up stability data, which must be submitted to the review agency in the form of official documen.

Generally, a convenient submission is made through the CDE "Applicant Window" for preliminary review, but the completion of the formal review needs to be based on a formal official docume.

The Food and Drug Administration returned the document

After the technical review is completed, CDE will send the review documents to the approval department for administrative approv.

The approval agency reviews and approves the documents submitted for approval, and if any problem is found, it usually communicates with the review agency and the approval agency for supplementary explanations, or returns it to the review agency for revision and improveme.

Those returned to the review agency are called "office return", and the corresponding procedures and time limit are not included in the registration management measur.

In the event of a "return from the bureau", CDE needs to return to the comprehensive review or professional review stage step by step in accordance with internal procedures, and then re-approval and submit it to the Food and Drug Administration after making corresponding revisio.

The reason for "rejection by the Bureau" may not necessarily be directly related to the applica.

The confusion caused by this process is indeed what the applicant needs to be.

The applicant needs to control their mentali.

I believe that the repeated occurrence is to ensure that the registration application is more compliant It is stable, and the applicant should actively cooperate with the completion of the "Office Refund" procedu.

In the future, if the regulatory authorities can disclose the processing standards and procedures of the bureau's return to the public, and incorporate the process of "the bureau's return" into the management within the time limit stipulated in the "Administrative Measures for Drug Registration", it will be very fair and helpful to the applica.

future outlook

From submitting the application for marketing authorization "to Beijing to take the test" to obtaining the "Gold List Title" of the approval document, it is the joy of the applicant after the arduous process of trying to meet the clinical drug nee.

It is hoped that peers in the industry can control and anticipate the regulations and registration procedures outside the regulations to help the drug listing process go smooth.