According to the guidance of the policy, whether it is to start multi-center clinical trials in China through overseas drugs, or to refer to the data of generic drugs from overseas listed drugs that are not listed in China, they are all promoting overseas clinically effective drugs. Speed ​​up the domestic listing. For domestic innovative drug companies, it is clear that the competitive pressure will be more obvious.

On April 30, 2020, the State Food and Drug Administration and the Center for Drug Evaluation released a number of drafts related to drug registration, which the industry dubbed the "May Day Gift Package". For overseas innovative drugs, improved drugs, traditional Chinese medicine compound prescriptions and high-end generic drugs with clinical needs, the policy is obviously favorable. And a series of process optimizations make the entire drug registration and production process more executable. This article mainly analyzes the categories of chemicals that are more affected.

01 Overseas listed drugs

Whether it is chemical drugs, traditional Chinese medicines or biological products, they are mainly classified according to the categories of innovative drugs, improved new drugs and generic drugs. However, chemical drugs also classify overseas-marketed drugs, that is, the former "imports", into independent categories. Now, whether traditional Chinese medicine or biological products are divided into overseas and domestic according to the specific situation.

In 2018, due to the recognition of overseas data and the favorable policies for the accelerated review and approval of overseas clinically urgently needed drugs, a large number of original research drugs marketed overseas in 2018 were launched in China.

According to the "Clinical Technical Requirements for Domestic and Unlisted Drugs Listed Overseas (Draft for Comment)" issued by CDE, according to the nature of drugs and ethnic differences, etc., 4 situations can be reduced/exempted from clinical trials, and 1 can be directly approved for marketing. .

Compared with the "Technical Guiding Principles for Acceptance of Overseas Clinical Trial Data of Drugs" issued by the State Food and Drug Administration in 2018, the draft for comments has a clear range of drugs that can be used, which is more executable.

Specifically, 3 of the 4 conditions that can be reduced/exempted from clinical trials are directly related to overseas original research drugs.

The first is that for foreign origin drugs that have been evaluated to be safe, effective and non-racially sensitive, exemption from clinical trials may be considered. When global data can support the safety and effectiveness of the drug, and there is no ethnic factor, foreign data can be accepted as one of the evidences to support the listing in China.

This kind of data can be directly approved for marketing if the global data of overseas originator drugs already contain data on PK, and/or PD, efficacy and safety of the Chinese population, and the analysis finds that the benefits of using them in Chinese patients outweigh the risks.

For overseas originating drugs that have been assessed as safe and effective but lack ethnic sensitivity data or existing data suggest ethnic sensitivity, relevant bridging clinical trials may be considered. Where there is a lack of global data on ethnic factors affecting relevant studies and data, necessary PK and/or PD, efficacy and safety studies should be carried out to support the marketing application of the drug. If global data can support the safety and efficacy of the drug, but there are ethnic factors that affect the evaluation of safety and efficacy, dose discovery and confirmatory clinical trials should be carried out to support the marketing application of the drug.

If the overseas originator drug is assessed to have insufficient safety and efficacy data, necessary exploratory and confirmatory clinical trials should be considered in accordance with the requirements of the new drug.

Overall, from a policy perspective, the State Food and Drug Administration encourages the simultaneous initiation of global clinical trials of new drugs marketed overseas.

The identity of an innovative drug can be obtained if it is simultaneously declared for listing in China before it is listed overseas. The benefits of the identity of an innovative drug mainly lie in data protection (monitoring).

Articles 33 and 34 of the 2016 edition of the Regulations on the Implementation of the Drug Administration Law of the People's Republic of China mentioned:

"In accordance with the requirements of protecting public health, the drug regulatory department of the State Council may set up a monitoring period of no more than 5 years for new drug varieties produced by drug manufacturers; during the monitoring period, no other enterprises may be approved for production and import"; Or the self-obtained and undisclosed test data and other data submitted by manufacturers or sellers licensed to sell drugs containing new chemical ingredients shall be protected, and no one shall make improper commercial use of the undisclosed test data and other data. Within 6 years from the date when the drug manufacturer or seller obtains the license certificate for the production and sale of new chemical ingredients, other applicants may apply for the production or sale of new chemical ingredients using the data in the preceding paragraph without the consent of the applicant who has obtained the license. If the drug is licensed, the drug supervision and administration department will not approve it; however, other applicants shall submit data obtained by themselves.

It can be seen that compared with the original research drugs that have been marketed overseas, the identity of innovative drugs has obvious inclination in policy.

According to the "Implementation Measures for Drug Trial Data Protection (Interim) (Draft for Comment)" issued by the Food and Drug Administration in 2018, the data protection period obtained by applying for the marketing of new drugs using overseas data but no clinical trial data of Chinese patients is sufficient for China to develop The data protection period obtained from the clinical trial data of 1/4 time; supplementary Chinese clinical trial data, corresponding to the data protection period of 1/2 time. However, the Implementation Measures for the Protection of Drug Trial Data (Interim) (Draft for Comment) has not yet been released in an official draft. Currently, the protection of drugs marketed overseas mainly comes from the protection of patents.

The accelerated launch of overseas original research drugs, on the one hand, is conducive to the availability of drugs for domestic patients, and on the other hand, it will inevitably form competition for new domestic drugs with the same target of me-too. Moreover, the medical insurance department may bid for new drugs with the same target to be included in the medical insurance based on the efficacy and price to control the number of places to enter the medical insurance catalog. The favorable policy of overseas original research drugs will inevitably create competitive pressure on domestic innovative drug companies.

The second is the addition of domestically marketed drugs to new overseas-approved indications.

If the original drug has been approved for a certain indication in China for more than 5 years, and other indications that have been approved overseas are added, a series of conditions need to be met at the same time. Therefore, when considering the use of overseas data to support the application of new indications, the in vitro antibacterial test of the drug against Chinese clinical isolates should also be carried out as one of the supporting evidences; the submitted clinical trial data can be verified on-site for clinical trials Or provide foreign advanced regulatory agencies (EU EMA, US FDA, Japan PMDA) to verify relevant supporting documents to support the authenticity, reliability and integrity of the clinical data, and may consider reducing or exempting clinical trials based on the evaluation of overseas clinical trial data.

It is worth noting that the number of domestically marketed drugs has increased the number of new indications that have been approved overseas, and the etiology and pathological changes of the disease are quite different (for example: anticoagulant drugs are used for cardiovascular diseases and lower extremity deep vein thrombosis diseases; immunosuppressants are used for skin diseases, digestive system diseases, rheumatic immune diseases, tumors, etc.); the efficacy of the original drug for different indications is quite different (for example, the efficacy of TNFα inhibitors in different indications is quite different), etc., usually not Support the use of overseas data to approve new indication applications.

In fact, the drugs that are currently used for off-label use in China, or the drugs that need to increase the number of new indications that have been approved overseas are anticoagulant drugs for cardiovascular diseases and lower extremity deep vein thrombosis diseases; immunosuppressants for skin diseases and digestive system diseases. , rheumatic immune diseases, tumor drugs. Among them, it has the greatest impact on anti-tumor drug companies. It is expected that in addition to tumors belonging to rare diseases, which can be recognized with overseas clinical data, the rest of the products will still have domestic clinical data.

The third type is that the single drugs of the overseas marketed compound drugs are all marketed in China.

The clinical trial data of Chinese patients and overseas clinical trial data of the listed single drug of this type of compound drug show that the benefits of the drug for Chinese patients outweigh the risks, and there is no obvious influence of ethnic factors compared with the overseas population data; The submitted overseas clinical trial research of the compound drug conforms to the relevant technical guidelines for clinical research of compound drugs at home and abroad, and the relevant clinical trial data can be used to fully evaluate its safety and effectiveness; the submitted clinical trial data can be used for clinical trial sites. Verified or provided foreign advanced regulatory agencies (EU EMA, US FDA, Japan PMDA) to verify relevant supporting documents to support the authenticity, reliability and integrity of the clinical data. It may be considered to reduce or exempt clinical trials based on the evaluation of overseas clinical trial data.

It is expected that the compound products of COPD, asthma, diabetes, hypertension and other products will be declared for listing in the short term if they have not been imported in China before.

02 Overseas modified medicines

In this draft of registration classification, both original research drugs and improved drugs that are marketed overseas are classified as category 5.1. In the past, there has been controversy as to whether the improved drugs listed overseas belong to category 5.1 or category 5.2. On the one hand, it does not belong to the original research drug, and on the other hand, it is not completely consistent with the original research drug, so it cannot completely belong to the generic drug.

Clinical advantages may become a stumbling block for overseas improved drugs, because foreign regulations do not have mandatory "clinical advantages", and the criteria for judging clinical advantages have not yet been clarified.

The "Clinical Technical Requirements for Domestic Unlisted Drugs Listed Overseas (Draft for Comment)" proposes the circumstances under which clinical trials can be reduced/exempted for domestically marketed drugs to add new dosage forms, new routes of administration, and new specifications of improved drugs that have been approved overseas: Original research The drug has been on the market in China for more than 5 years, and new dosage forms, new routes of administration, and new specifications are added for the approved indications of the original drug, such as the clinical trial data of Chinese patients and the data of overseas clinical trials completed for the original drug on the market at the same time. , the benefits of the drug for Chinese patients outweigh the risks, and there is no obvious influence of ethnic factors compared with the data of the overseas population; the submitted overseas clinical trial data of the new dosage form, new route of administration and new specification of the compound can be used for full evaluation Its safety and efficacy for the same indication population; the submitted clinical trial data can be verified on the clinical trial site or provided with foreign advanced regulatory agencies (EU EMA, US FDA, Japan PMDA) to verify relevant supporting documents to support the The clinical data is true, reliable and complete, and it may be considered to reduce or exempt clinical trials based on the evaluation of overseas clinical trial data.

It can be seen that if the overseas improved drug is thoroughly researched abroad, it is still very possible to reduce or exempt clinical trials in China, but if the clinical data is only non-inferior and has no advantages compared with the original research, whether it can improve the compliance of patients with drug administration, reduce Adverse reactions, the benefits to the patient outweigh the risks and other reasons as the basis for the question. Otherwise, if the water is clear, there will be no fish, and products that can achieve significant clinical advantages by changing the dosage form may be more difficult than innovative drugs.

03 Generic drugs

If there is sufficient evidence to prove that an overseas original research drug is ineffective or has serious safety problems, it will not be approved for clinical trials in China. It is worth noting that the consultation draft mentioned that the source of clinical data is not only concerned with registered clinical trial data, but also post-marketing clinical data, including the dynamic evaluation of original research drugs by foreign regulatory agencies. Therefore, when a domestic generic drug product is approved, it must consider whether the product has been delisted overseas, especially whether the product that has been delisted from the market is worth the project.

The consultation draft has a new direction for the clinical trial requirements of generic drugs that have been marketed overseas and domestically unlisted drugs, and answers the question about how to conduct clinical trials of the new three types of drugs. Two factors, the clinical evaluation results of the original drug and the formulations, need to be considered. Based on the results of the clinical evaluation of the original drug, the considerations for conducting the necessary clinical trials of Chinese patients are consistent with the requirements for the clinical trials of the original drug. This means that the clinical data of the new three types of generic drugs can be "referenced" to the original research drugs that have been marketed overseas. Whether supplementary pharmacology and clinical research materials are needed depends on the research and development quality of the original research drugs marketed overseas.

For chemical generic drugs, the changes in this regulation are mainly in terms of process. For example, the application for registration of generic drugs should, in principle, be submitted after the selected reference preparation is included in the published catalogue of reference preparations. The selected reference preparation is not included in the list. For the catalogue of reference preparations, it should communicate with the Center for Drug Evaluation and reach an agreement before submitting the application. This means that someone in the industry has a clear idea of ​​which generic drug is being made, and companies can also complete the pharmaceutical research and development first and declare the reference product within a reasonable time before the start of the bioequivalence study. Companies can gain time but face The risk that the selected reference product may not be approved is expected to be avoided by the company through communication.

Chemical APIs used to imitate domestically marketed drugs can apply for separate review and approval. The review time limit for chemical APIs that apply for separate review and approval is 200 working days. The approval of such APIs is conducive to breaking the preparation-raw material integration enterprise Control over raw materials.

The clarification of the process of changing the suppliers of APIs can be regarded as the highlight of this time. The suppliers of changing APIs used in preparations are classified into major changes and moderate changes according to risk. The physical properties and impurity status of the API in the medium change should be consistent and have no impact on the quality of the preparation. A moderate change requires a comprehensive quality comparison study of the API before and after the change, and the method used in the study needs to be verified, focusing on comparing the impurities of the API before and after the change, and indicators related to the absorption and efficacy of the API and the preparation in vivo (such as crystal form). , particle size distribution, molecular weight distribution, viscosity, etc.) and so on. Carry out quality comparison research on the preparations prepared with the raw materials before and after the change, focusing on proving that the dissolution/release behavior of the samples before and after the change, or the important physical and chemical properties and indicators related to in vivo absorption and efficacy, and the status of impurities are consistent. Three batches of preparations continuously produced with the changed API were inspected. Accelerated and long-term stability investigations shall be carried out on a batch of preparations produced with the changed APIs, and the stability study data of not less than 3 months shall be provided at the time of application, and the stability of the products before the change shall be compared.

If the physical properties and impurity status of the API are not consistent, it is a major change that affects the quality of the preparation. If necessary, the in vivo bioequivalence study should be considered. This means that as long as the supplier of the changed API is a moderate change, it is expected that the in vivo bioequivalence study is not required, which means that the non-preparation-raw material company may be the API manufacturer of 2 or more companies when applying for registration. The products should be reported and filed at the same time.