• Drugs that have been marketed overseas (not yet in China)

Whether it is chemical drugs, traditional Chinese medicines or biological products, they are mainly classified according to the classification of innovative new drugs, improved new drugs and generic drugs. Traditional Chinese medicines and biological products both have the overseas and domestic classification according to specific situations, while chemical drugs that have been marketed overseas are classified independently.

In the “Clinical Trial Technical Requirements for Drugs that Have Been Marketed Overseas but Not yet in China (Draft for Public Review)”, CDE has listed 4 types of scenarios whereby clinical trials can be exempted and another whereby the drug can be directly approved for marketing depending on the characteristics of the drugs and racial differences.

Specifically, three of the four types of criteria where clinical trials can be reduced or exempted directly are related to overseas original drugs.

Exemptions (Criteria 1)

The first criteria for exemption of clinical trials is that after evaluation the original drug is safe, effective without racial sensitivity. The overseas data can be accepted as one of evidences for China market approval, if global data support the safety, efficacy, and when there is no racial influence at the same time.

If the global data of the original research already contain PK and/or PD, safety and efficacy data of the Chinese population, and it is analyzed that the benefits for Chinese patients are greater than the risks, it can be directly approved for marketing.

If the original overseas drug is evaluated to be safe and effective, but lacks racial sensitivity data or data show there is racial sensitivity, relevant bridging clinical trials may be considered to conduct. If the global data lack relevant researches and data of racial differences, it is required to conduct PK and/or PD, efficacy and safety researches to support marketing approval. If global data can support the safety and efficacy of the drug, but due to racial factors have influence on the safety and efficacy evaluation, then dosage exploratory and confirmatory clinical trials shall be conducted to support the drug’s marketing application.

If the safety and efficacy data of original overseas drug is evaluated to be insufficient, it’s mandatory to conduct exploratory and confirmatory clinical trials according to the requirements of NDA application.

On the whole, from a policy perspective, China NMPA encourages the overseas innovative new drugs that have been approved overseas to conduct global clinical trials simultaneously.

If a drug that has not been approved overseas applies for China market approval simultaneously, the drug can be classified as an innovative new drug, which can benefit from data protection (monitoring) for 5 years, meaning this drug have 5 years of exclusivity in China.

Exemptions (Criteria 2)

The second criteria: China approved marketed drugs that have been approved overseas for new indications.

If the original drug has been approved for one indication for over 5 years, a series of conditions shall be met for the additional indication which has been approved overseas.

Therefore, when considering the overseas data as a support of new indication application, applicant shall also conduct in vitro antibacterial test for Chinese clinical isolates. The submitted clinical trial data can be on-site inspected or can be inspected by FDA, EMA and PMDA, in order to support the authenticity, liability and integrity of the clinical data. The clinical trial can be reduced or exempted based on the evaluation situation of overseas clinical trial data.

Please note that if the differences of disease etiology and pathological changes are significant, the efficacy of original drugs for different indications are quite different, then the overseas data for application of new indication is not applicable.

Exemptions (Criteria 3)

The third criteria is for the single drugs of overseas compound drugs are all marketed and approved in China.

The Chinese patients clinical trial data and overseas clinical trial data of the single drugs have been marketed show that, the benefits of this single drugs for Chinese patients are greater than the risks and there is no obvious racial factor compared with the data of overseas population. The submitted overseas clinical trial study of this compound drug shall conform to the relevant technical guidelines of China and foreign countries, and the relevant clinical trial data can be used for evaluating the drug’s safety and efficacy sufficiently. The submitted clinical trial data can be on-site inspected or can be inspected by FDA, EMA and PMDA, in order to support the authenticity, liability and integrity of the clinical data. Based on above situations, the clinical trials can be reduced or exempted.

• Overseas improved drugs

This draft for public review of registration classification has classified overseas approved original drugs and improved drugs as class 5.1 in China.

The “Clinical Technical Requirements for Drugs that Are Marketed Overseas Already But Not Marketed in China (Draft for Public Review)” proposes the situations of clinical trial reduction/exemption for improved drugs marketed already includes the addition of new dosage form, new administration routes and new strengths as follows:

If the original drug has been already marketed for over 5 years, the situations of additional new dosage form, new administration routes and new strengths for approved indication of original drug like the clinical trial study data of Chinese and overseas patients shows that, the benefit of this drug outweighs risks on Chinese patients and racial influence cannot be obviously observed compared with the data of overseas population. The submitted overseas clinical trial data of new dosage form, new administration route and new strength of the compound can be on-site inspected or can be inspected by FDA, EMA and PMDA, in order to support the authenticity, liability and integrity of the clinical data. Based on above situations, the clinical trials can be reduced or exempted.

• Generic drugs

If there are sufficient evidences to prove that the overseas original overseas drug has no efficacy or serious safety problem, then conducting clinical trial in China shall not be approved. It is worth noting that the draft for public review mentioned that the clinical data resources not only focus on registered clinical trial data, but also post-marketing clinical data including the dynamic evaluation of original drug by foreign regulatory agencies.

• API (Active Pharmaceutical Ingredients) Policy Improvements

The APIs of finished drugs that have been already marketed in China can apply for separated review and approval, and approval timeline is 200wds.

API Supplier Change Improvements

The clarification of the process of changing API supplier is one of the highlights of this draft for public review. Based on risks, changing suppliers of APIs can be classified as major change and medium change.

For the medium change, the physical property and impurity of API shall be consistent and shall have no influence on the quality of the preparations.

A comprehensive quality comparison research of API shall be conducted. And it is required to verify the method of this research, which emphasizes on comparing whether the impurity of API, the indexes (such as crystal form, size distribution, molecular weight distribution and viscosity) related to in vivo absorption and efficacy of API and preparation before and after change remains consistent.

The quality comparison research of preparations shall prove importantly that the dissolution/release testings of samples, or the significant physicochemical properties and indexes, and impurity related to in vivo absorption and efficacy are consistent before and after the change.

The consecutive 3 batches of preparations manufactured by the API after change shall be tested. The 1 batch of preparation manufactured by the changed API shall be conducted an accelerated and long-term stability observation, and it is required to provide stability study materials of over 3 months which has also been compared with that of the preparation before change when submitting application.

If the physical properties and impurity of the API are inconsistent before and after change, the impact on the quality of the preparation is a major change. For a major change, in vivo bioequivalence study shall be conducted when necessary. This means it’s unnecessary to conduct in vivo bioequivalence study for suppliers who change APIs if they are medium change, also means non-preparation-API enterprises may have two or more API enterprises file simultaneously for the same API product.

This article is originally translated from Y-LP.com.

A: Under the current background of the classification of chemical drugs, it’s unlikely for overseas OTC products to obtain approval from NMPA successfully. The main reason is that OTC is neither a category of innovative drugs, nor can it be applied strictly according to the concept of generic drugs. As there’s no definite original product, it’s difficult to develop OTC products according to the conceptual framework of general generic drugs.

Q10: What is significance of the implementation of the communication meeting policy for applicants?

A: The implementation of communication meeting policy is originated from “NMPA Announcement on Issuing Administration Law of Drug Development and Technical Review Communication” (No.74, 2018). This announcement stipulated that it is applicable to initiate the communication meeting relating to innovative drugs, improved new drugs, biosimilars, complex generic drugs and consistency evaluation products in the process of development and registration application. Generally, applicants will propose actively to apply for communication meeting. The main issues of application product could be solved previously by the CDE meeting or written letter, phone response from CDE, in order to accelerate the process of market approval.

Q11: What is “Catalogue of Chemical Drugs” and its value?

A: “Catalogue of Chemical Drugs” is also named as “Catalogue of China Marketed Drugs”, which is issued on Dec 29th, 2017. The catalogue has recorded the drugs with safety, efficacy and controllable quality, and confirmed RLD and RS (is short for Reference Standard). Similar to the Orange Book of FDA and PMDA, “Catalogue of Chemical Drugs” provides a good reference for the ongoing consistency evaluation work of chemical drugs in China.

Q12: What is the difference between the current trial of No.80 and “The applicant submits an application for approval of drug as Marketing Authorization Holder (MAH) after completing studies on pharmacy, pharmacotoxicology and clinical trials to support drug approval, confirming specifications, completing production process validation of commercial scale, and preparing to undergo drug registration inspection and testing, the applicant shall apply for market approval” mentioned in the new “Provisions”? Are there any new requirements in the new “Provisions”?

A: The implementation of this clause is clearly inconsistent with the specific requirements in current trial No.80 promulgated in May 2016 namely, “Requirements for application materials of chemical drugs’ new registration classification”. The chapter of process validation and evaluation of 3.2.P.3.5 in No.80 has mentioned that for non-sterile process procedure, applicant could submit the process validation report (No:_ , Version: ), or the process validation protocol (No: , Version: _) and commitment contract of the first three commercial production batches’ validation after marketing. As the conflicted situation, the No.80 might need to be subject to the current new “Provisions”.

Q13: How to understand the Article 35 of generic drugs, in vitro diagnostic reagents in accordance with drug management and other eligible conditions in “Provisions” that “The applicant can apply for drug market approval directly, after the evaluation by the applicant, and deems it unnecessary or impossible to conduct a clinical trial and conforms to the conditions of clinical trial exemption. The technical guidelines and relevant requirements of clinical trial exemptions are formulated and issued by the Center for Drug Evaluation (CDE)”? And how to understand and implement this in actual projects?

A: Currently this article has not been implemented yet. According to the article, the applicant could apply directly for market approval, after evaluating there’s no need to conduct clinical trial. Based on this, many imported injection of class 5.2 could apply for market approval directly from July 1st .2020.

However, the current actual situation is class 3 and 4 of chemical drugs can apply for production directly. As for imported class 5 chemical drugs, there are mainly two situations which can apply for market approval directly: (1) the class 5.2 oral solid preparations have completed BE study or have the BE study approved overseas can apply, (2) rare diseases and other conditions can apply for market approval directly. The process of clinical application firstly and then market approval is still work for other products.

Q14: How to understand the term “based on risks” that has been mentioned many times in the new “Provisions”?

A: “Based on risks” is frequency mentioned both in regulations and laws and the communications with CDE in these two years, which makes the review and approval more flexible than before. In the past, whether high risk products like class 5.1 injection or super low risk products like pharmaceutical excipients in topic use preparations will be issued a “Registration Inspection Notice”. Understandably, this causes a heavy burden on the resources of the national inspection center. The “Provisions” has further consolidated the industry reform of theses years, and is still being improved continuously.

Q15: What are the highlights of the registration inspection link in the new “Provisions”?

A: The biggest highlight is the applicant can decide to whether to apply for registration inspection in advance based on its product according to relevant clauses. If the product has a high risk, the possibility of registration inspection is very high. The applicant may propose the application in advance in order to ensure the registration inspection could be completed in time successfully.

Q16: What is the purpose and significance of adding chapter “Accelerated Drug Market Registration Procedure” in the new “Provisions”?

A: The “Chapter 4, Accelerated Drug Market Registration Procedure” has established four accelerated channels for breakthrough therapeutic drug procedure, approval procedure with condition, priority review&approval procedure and special review&approval procedure. Among them, breakthrough therapeutic drug procedure and approval procedure with condition are mainly for products in clinical trial phases. Priority review&approval procedure is applicable for products in market approval step. NMPA can decide to conduct special review&approval for drugs required for public health emergency, in the event of a threat from a public health emergency or after a public health emergency occurs in accordance with law.

For China drug regulatory or registration queries, you may contact us: info@accestra.com

This article is originally translated from Canny.

Glossary:

RLD Reference Listed Drug
RS Reference Standard

Taking in to account the important role of medicines in combating Covid-19. After investigation, CDE has decided to adjust the submission time and form of certifications of imported drugs (including clinical trial applications, marketing registration application, supplementary application and re-registration application) in order to ensure the smooth progress of imported drugs’ registration application. The details are as follows:

For the overseas drugs which cannot be notarized in foreign countries notarized or posted, the overseas holder or domestic registration agency shall illustrate in the special statement part of drug application form and submit electronically scanned version of certifications. In the statement, the applicant shall make a commitment to bear the corresponding legal responsibility of its authenticity, validity and consistency of original notarized certifications, and also promise that the original notarized certifications will be submitted completely before approval.

The registration applications according with the above situation could be accepted by CDE. The applicant shall take the responsibility of the rejection for not supplementing original notarized certifications according to relevant requirements before approval.

In addition, the electronic certifications issued by overseas drug administration departments will be approved.

The above content will be implemented since the release date. The time for normal submission time of certifications will be notified according to the pandemic situation.

Release Date: 2020.05.13