On April 30, 2020, China NMPA and CDE have issued a number of draft policies for public review relating to China drug registration. The policies announced have obviously favorable benefits for clinical needed overseas innovative new drugs, improved drugs, traditional Chinese medicine compound preparations and high-end generic drugs. And a series of improved procedures make the whole process of drug registration and production more executable. This article is mainly an analysis of some categories of chemical drugs that are most likely to benefit.
- 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.